Beyond the tumor microenvironment: Orchestrating systemic T‑cell response for next‑generation cancer immunotherapy (Review)

Anagnostou V, Niknafs N, Marrone K, Bruhm DC, White JR, Naidoo J, Hummelink K, Monkhorst K, Lalezari F, Lanis M, et al: Multimodal genomic features predict outcome of immune checkpoint blockade in non-small-cell lung cancer. Nat Cancer. 1:99–111. 2020. View Article : Google Scholar

Wu B, Zhang B, Li B, Wu H and Jiang M: Cold and hot tumors: From molecular mechanisms to targeted therapy. Signal Transduct Target Ther. 9:2742024. View Article : Google Scholar :

Yu Y, Zeng D, Ou Q, Liu S, Li A, Chen Y, Lin D, Gao Q, Zhou H, Liao W and Yao H: Association of survival and immune-related biomarkers with immunotherapy in patients with non-small cell lung cancer: A meta-analysis and individual patient-level analysis. JAMA Netw Open. 2:e1968792019. View Article : Google Scholar

Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, Gherardini PF, Prestwood TR, Chabon J, Bendall SC, et al: Systemic immunity is required for effective cancer immunotherapy. Cell. 168:487–502.e15. 2017. View Article : Google Scholar

Tselikas L, Dardenne A, de Baere T, Faron M, Ammari S, Farhane S, Suzzoni S, Danlos FX, Raoult T, Susini S, et al: Feasibility, safety and efficacy of human intra-tumoral immuno-therapy. Gustave Roussy's initial experience with its first 100 patients. Eur J Cancer. 172:1–12. 2022. View Article : Google Scholar

Spranger S: Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int Immunol. 28:383–391. 2016. View Article : Google Scholar :

Sadeghi Rad H, Monkman J, Warkiani ME, Ladwa R, O'Byrne K, Rezaei N and Kulasinghe A: Understanding the tumor microenvironment for effective immunotherapy. Med Res Rev. 41:1474–1498. 2021. View Article : Google Scholar :

Casalegno Garduño R, Spitschak A, Pannek T and Pützer BM: CD8+ T cell subsets as biomarkers for predicting checkpoint therapy outcomes in cancer immunotherapy. Biomedicines. 13:9302025. View Article : Google Scholar

Loi S, Adams S, Schmid P, Cortés J, Cescon DW, Winer EP, Toppmeyer DL, Rugo HS, De Laurentiis M, Nanda R, et al: LBA13-Relationship between tumor infiltrating lymphocyte (TIL) levels and response to pembrolizumab (pembro) in metastatic triple-negative breast cancer (mTNBC): Results from KEYNOTE-086. Ann Oncol. 28(Suppl 5): v6082017. View Article : Google Scholar

Hegde PS and Chen DS: Top 10 challenges in cancer immunotherapy. Immunity. 52:17–35. 2020. View Article : Google Scholar : PubMed/NCBI

Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, Berent-Maoz B, Pang J, Chmielowski B, Cherry G, et al: Genomic and transcriptomic features of response to Anti-PD-1 therapy in metastatic melanoma. Cell. 165:35–44. 2016. View Article : Google Scholar : PubMed/NCBI

Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel EE III, Koeppen H, Astarita JL, Cubas R, et al: TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 554:544–548. 2018. View Article : Google Scholar

Cascio S, Chandler C, Zhang L, Sinno S, Gao B, Onkar S, Bruno TC, Vignali DAA, Mahdi H, Osmanbeyoglu HU, et al: Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition. Sci Adv. 7:eabi57902021. View Article : Google Scholar : PubMed/NCBI

Grout JA, Sirven P, Leader AM, Maskey S, Hector E, Puisieux I, Steffan F, Cheng E, Tung N, Maurin M, et al: Spatial positioning and matrix programs of cancer-associated fibroblasts promote T-cell exclusion in human lung tumors. Cancer Discov. 12:2606–2625. 2022. View Article : Google Scholar : PubMed/NCBI

Elyada E, Bolisetty M, Laise P, Flynn WF, Courtois ET, Burkhart RA, Teinor JA, Belleau P, Biffi G, Lucito MS, et al: Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9:1102–1123. 2019. View Article : Google Scholar : PubMed/NCBI

Griffioen AW, Damen CA, Blijham GH and Groenewegen G: Tumor angiogenesis is accompanied by a decreased inflammatory response of tumor-associated endothelium. Blood. 88:667–673. 1996. View Article : Google Scholar

Nagl L, Horvath L, Pircher A and Wolf D: Tumor endothelial cells (TECs) as potential immune directors of the tumor microenvironment-new findings and future perspectives. Front Cell Dev Biol. 8:7662020. View Article : Google Scholar

Sahu A, Kose K, Kraehenbuehl L, Byers C, Holland A, Tembo T, Santella A, Alfonso A, Li M, Cordova M, et al: In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response. Nat Commun. 13:53122022. View Article : Google Scholar

Subramanian M, Kabir AU, Barisas D, Krchma K and Choi K: Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy. Cell Rep Med. 4:1008962023. View Article : Google Scholar : PubMed/NCBI

Steele MM, Jaiswal A, Delclaux I, Dryg ID, Murugan D, Femel J, Son S, du Bois H, Hill C, Leachman SA, et al: T cell egress via lymphatic vessels is tuned by antigen encounter and limits tumor control. Nat Immunol. 24:664–675. 2023. View Article : Google Scholar : PubMed/NCBI

Huang CX, Lao XM, Wang XY, Ren YZ, Lu YT, Shi W, Wang YZ, Wu CY, Xu L, Chen MS, et al: Pericancerous cross-presentation to cytotoxic T lymphocytes impairs immunotherapeutic efficacy in hepatocellular carcinoma. Cancer Cell. 42:2082–2097.e10. 2024. View Article : Google Scholar

Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, et al: Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: Prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 21:1353–1365. 2020. View Article : Google Scholar : PubMed/NCBI

Cristescu R, Aurora-Garg D, Albright A, Xu L, Liu XQ, Loboda A, Lang L, Jin F, Rubin EH, Snyder A and Lunceford J: Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: A pan-tumor retrospective analysis of participants with advanced solid tumors. J Immunother Cancer. 10:e0030912022. View Article : Google Scholar : PubMed/NCBI

Ricciuti B, Wang X, Alessi JV, Rizvi H, Mahadevan NR, Li YY, Polio A, Lindsay J, Umeton R, Sinha R, et al: Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels. JAMA Oncol. 8:1160–1168. 2022. View Article : Google Scholar : PubMed/NCBI

Baharom F, Ramirez-Valdez RA, Khalilnezhad A, Khalilnezhad S, Dillon M, Hermans D, Fussell S, Tobin KKS, Dutertre CA, Lynn GM, et al: Systemic vaccination induces CD8⁺ T cells and remodels the tumor microenvironment. Cell. 185:4317–4332.e15. 2022. View Article : Google Scholar

Zheng M: Tumor mutation burden for predicting immune checkpoint blockade response: The more, the better. J Immunother Cancer. 10:e0030872022. View Article : Google Scholar

McGrail DJ, Pilié PG, Rashid NU, Voorwerk L, Slagter M, Kok M, Jonasch E, Khasraw M, Heimberger AB, Lim B, et al: High tumor mutation burden fails to predict immune checkpoint blockade response across all cancer types. Ann Oncol. 32:661–672. 2021. View Article : Google Scholar : PubMed/NCBI

Niknafs N, Balan A, Cherry C, Hummelink K, Monkhorst K, Shao XM, Belcaid Z, Marrone KA, Murray J, Smith KN, et al: Persistent mutation burden drives sustained anti-tumor immune responses. Nat Med. 29:440–449. 2023. View Article : Google Scholar : PubMed/NCBI

Valpione S, Mundra PA, Galvani E, Campana LG, Lorigan P, De Rosa F, Gupta A, Weightman J, Mills S, Dhomen N and Marais R: The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival. Nat Commun. 12:40982021. View Article : Google Scholar : PubMed/NCBI

Meier SL, Satpathy AT and Wells DK: Bystander T cells in cancer immunology and therapy. Nat Cancer. 3:143–155. 2022. View Article : Google Scholar : PubMed/NCBI

Simoni Y, Becht E, Fehlings M, Loh CY, Koo SL, Teng KWW, Yeong JPS, Nahar R, Zhang T, Kared H, et al: Bystander CD8⁺ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 557:575–579. 2018. View Article : Google Scholar : PubMed/NCBI

Chen X, Zhao J, Yue S, Li Z, Duan X, Lin Y, Yang Y, He J, Gao L, Pan Z, et al: An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy. Nat Cancer. 5:1063–1081. 2024. View Article : Google Scholar : PubMed/NCBI

Lowery FJ, Krishna S, Yossef R, Parikh NB, Chatani PD, Zacharakis N, Parkhurst MR, Levin N, Sindiri S, Sachs A, et al: Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers. Science. 375:877–884. 2022. View Article : Google Scholar : PubMed/NCBI

Meng Z, Rodriguez Ehrenfried A, Tan CL, Steffens LK, Kehm H, Zens S, Lauenstein C, Paul A, Schwab M, Förster JD, et al: Transcriptome-based identification of tumor-reactive and bystander CD8⁺ T cell receptor clonotypes in human pancreatic cancer. Sci Transl Med. 15:eadh95622023. View Article : Google Scholar

Kortekaas KE, Santegoets SJ, Sturm G, Ehsan I, van Egmond SL, Finotello F, Rajanoski Z, Welters MJP, van Poelgeest MIE and van der Burg SH: CD39 identifies the CD4⁺ tumor-specific T-cell population in human cancer. Cancer Immunol Res. 8:1311–1321. 2020. View Article : Google Scholar

Duhen T, Duhen R, Montler R, Moses J, Moudgil T, de Miranda NF, Goodall CP, Blair TC, Fox BA, McDermott JE, et al: Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat Commun. 9:27242018. View Article : Google Scholar

Qiao M, Zhou F, Liu X, Jiang T, Wang H, Jia Y, Li X, Zhao C, Cheng L, Chen X, et al: Interleukin-10 induces expression of CD39 on CD8+T cells to potentiate anti-PD1 efficacy in EGFR-mutated non-small cell lung cancer. J Immunother Cancer. 10:e0054362022. View Article : Google Scholar : PubMed/NCBI

Webb JR, Milne K and Nelson BH: PD-1 and CD103 are widely coexpressed on prognostically favorable intraepithelial CD8 T cells in human ovarian cancer. Cancer Immunol Res. 3:926–935. 2015. View Article : Google Scholar : PubMed/NCBI

Corgnac S, Malenica I, Mezquita L, Auclin E, Voilin E, Kacher J, Halse H, Grynszpan L, Signolle N, Dayris T, et al: CD103⁺CD8⁺ TRM cells accumulate in tumors of anti-PD-1-responder lung cancer patients and are tumor-reactive lymphocytes enriched with Tc17. Cell Rep Med. 1:1001272020. View Article : Google Scholar

Wang Z, Ahmed S, Labib M, Wang H, Wu L, Bavaghar-Zaeimi F, Shokri N, Blanco S, Karim S, Czarnecka-Kujawa K, et al: Isolation of tumour-reactive lymphocytes from peripheral blood via microfluidic immunomagnetic cell sorting. Nat Biomed Eng. 7:1188–1203. 2023. View Article : Google Scholar : PubMed/NCBI

Gallerano D, Ciminati S, Grimaldi A, Piconese S, Cammarata I, Focaccetti C, Pacella I, Accapezzato D, Lancellotti F, Sacco L, et al: Genetically driven CD39 expression shapes human tumor-infiltrating CD8⁺ T-cell functions. Int J Cancer. 147:2597–2610. 2020. View Article : Google Scholar : PubMed/NCBI

Laumont CM, Wouters MCA, Smazynski J, Gierc NS, Chavez EA, Chong LC, Thornton S, Milne K, Webb JR, Steidl C and Nelson BH: Single-cell profiles and prognostic impact of tumor-infiltrating lymphocytes coexpressing CD39, CD103, and PD-1 in ovarian cancer. Clin Cancer Res. 27:4089–4100. 2021. View Article : Google Scholar : PubMed/NCBI

He J, Xiong X, Yang H, Li D, Liu X, Li S, Liao S, Chen S, Wen X, Yu K, et al: Defined tumor antigen-specific T cells potentiate personalized TCR-T cell therapy and prediction of immunotherapy response. Cell Res. 32:530–542. 2022. View Article : Google Scholar

Liu B, Zhang Y, Wang D, Hu X and Zhang Z: Single-cell meta-analyses reveal responses of tumor-reactive CXCL13⁺ T cells to immune-checkpoint blockade. Nat Cancer. 3:1123–1136. 2022. View Article : Google Scholar

Hanada KI, Zhao C, Gil-Hoyos R, Gartner JJ, Chow-Parmer C, Lowery FJ, Krishna S, Prickett TD, Kivitz S, Parkhurst MR, et al: A phenotypic signature that identifies neoantigen-reactive T cells in fresh human lung cancers. Cancer Cell. 40:479–493.e6. 2022. View Article : Google Scholar : PubMed/NCBI

Dai S, Zeng H, Liu Z, Jin K, Jiang W, Wang Z, Lin Z, Xiong Y, Wang J, Chang Y, et al: Intratumoral CXCL13⁺CD8⁺T cell infiltration determines poor clinical outcomes and immunoevasive contexture in patients with clear cell renal cell carcinoma. J Immunother Cancer. 9:e0018232021. View Article : Google Scholar

Aoki T, Chong LC, Takata K, Milne K, Marshall A, Chavez EA, Miyata-Takata T, Ben-Neriah S, Unrau D, Telenius A, et al: Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma. Proc Natl Acad Sci USA. 118:e21058221182021. View Article : Google Scholar :

Eiva MA, Omran DK, Chacon JA and Powell DJ Jr: Systematic analysis of CD39, CD103, CD137, and PD-1 as biomarkers for naturally occurring tumor antigen-specific TILs. Eur J Immunol. 52:96–108. 2022. View Article : Google Scholar :

Parkhurst M, Gros A, Pasetto A, Prickett T, Crystal JS, Robbins P and Rosenberg SA: Isolation of T-cell receptors specifically reactive with mutated tumor-associated antigens from tumor-infiltrating lymphocytes based on CD137 expression. Clin Cancer Res. 23:2491–2505. 2017. View Article : Google Scholar

Yost KE, Satpathy AT, Wells DK, Qi Y, Wang C, Kageyama R, McNamara KL, Granja JM, Sarin KY, Brown RA, et al: Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med. 25:1251–1259. 2019. View Article : Google Scholar

Tonnerre P, Wolski D, Subudhi S, Aljabban J, Hoogeveen RC, Damasio M, Drescher HK, Bartsch LM, Tully DC, Sen DR, et al: Differentiation of exhausted CD8⁺ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nat Immunol. 22:1030–1041. 2021. View Article : Google Scholar : PubMed/NCBI

Watowich MB, Gilbert MR and Larion M: T cell exhaustion in malignant gliomas. Trends Cancer. 9:270–292. 2023. View Article : Google Scholar : PubMed/NCBI

Beltra JC, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, Casella V, Ngiow SF, Khan O, Huang YJ, et al: Developmental relationships of four exhausted CD8⁺ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity. 52:825–841.e8. 2020. View Article : Google Scholar

Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, Tsao HW, Godec J, LaFleur MW, Brown FD, et al: The epigenetic landscape of T cell exhaustion. Science. 354:1165–1169. 2016. View Article : Google Scholar : PubMed/NCBI

Zhang Z, Chen L, Chen H, Zhao J, Li K, Sun J and Zhou M: Pan-cancer landscape of T-cell exhaustion heterogeneity within the tumor microenvironment revealed a progressive roadmap of hierarchical dysfunction associated with prognosis and therapeutic efficacy. EBioMedicine. 83:1042072022. View Article : Google Scholar : PubMed/NCBI

Wu Z, Yoshikawa T, Inoue S, Ito Y, Kasuya H, Nakashima T, Zhang H, Kotaka S, Hosoda W, Suzuki S and Kagoya Y: CD83 expression characterizes precursor exhausted T cell population. Commun Biol. 6:2582023. View Article : Google Scholar : PubMed/NCBI

Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, Danilo M, Alfei F, Hofmann M, Wieland D, et al: T cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections. Immunity. 45:415–427. 2016. View Article : Google Scholar

Kim CG, Kim G, Kim KH, Park S, Shin S, Yeo D, Shim HS, Yoon HI, Park SY, Ha SJ and Kim HR: Distinct exhaustion features of T lymphocytes shape the tumor-immune microenvironment with therapeutic implication in patients with non-small-cell lung cancer. J Immunother Cancer. 9:e0027802021. View Article : Google Scholar : PubMed/NCBI

Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, Held W, Zehn D, Hofmann M and Thimme R: TCF1⁺ hepatitis C virus-specific CD8⁺ T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 8:150502017. View Article : Google Scholar

Jadhav RR, Im SJ, Hu B, Hashimoto M, Li P, Lin JX, Leonard WJ, Greenleaf WJ, Ahmed R and Goronzy JJ: Epigenetic signature of PD-1+ TCF1+ CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Proc Natl Acad Sci USA. 116:14113–14118. 2019. View Article : Google Scholar : PubMed/NCBI

Li X, Li Y, Dong L, Chang Y, Zhang X, Wang C, Chen M, Bo X, Chen H, Han W and Nie J: Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models. J Clin Invest. 133:e1656732023. View Article : Google Scholar : PubMed/NCBI

Nagasaki J, Inozume T, Sax N, Ariyasu R, Ishikawa M, Yamashita K, Kawazu M, Ueno T, Irie T, Tanji E, et al: PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes. Cell Rep. 38:1103312022. View Article : Google Scholar

Codarri Deak L, Nicolini V, Hashimoto M, Karagianni M, Schwalie PC, Lauener L, Varypataki EM, Richard M, Bommer E, Sam J, et al: PD-1-cis IL-2R agonism yields better effectors from stem-like CD8⁺ T cells. Nature. 610:161–172. 2022. View Article : Google Scholar : PubMed/NCBI

Hashimoto M, Araki K, Cardenas MA, Li P, Jadhav RR, Kissick HT, Hudson WH, McGuire DJ, Obeng RC, Wieland A, et al: PD-1 combination therapy with IL-2 modifies CD8⁺ T cell exhaustion program. Nature. 610:173–181. 2022. View Article : Google Scholar :

Ren Z, Zhang A, Sun Z, Liang Y, Ye J, Qiao J, Li B and Fu YX: Selective delivery of low-affinity IL-2 to PD-1+ T cells rejuvenates antitumor immunity with reduced toxicity. J Clin Invest. 132:e1536042022. View Article : Google Scholar

Zehn D, Thimme R, Lugli E, de Almeida GP and Oxenius A: 'Stem-like' precursors are the fount to sustain persistent CD8⁺ T cell responses. Nat Immunol. 23:836–847. 2022. View Article : Google Scholar

Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV, LaFleur MW, Yates KB, Lako A, Felt K, Naik GS, et al: Subsets of exhausted CD8⁺ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat Immunol. 20:326–336. 2016. View Article : Google Scholar

Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, Shan Q, Hale JS, Lee J, Nasti TH, et al: Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 537:417–421. 2016. View Article : Google Scholar

Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, Carmona SJ, Scarpellino L, Gfeller D, Pradervand S, et al: Intratumoral Tcf1⁺PD-1⁺CD8⁺ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity. 50:195–211.e10. 2019. View Article : Google Scholar

Tabanelli V, Melle F, Motta G, Mazzara S, Fabbri M, Agostinelli C, Calleri A, Del Corvo M, Fiori S, Lorenzini D, et al: The identification of TCF1+ progenitor exhausted T cells in THRLBCL may predict a better response to PD-1/PD-L1 blockade. Blood Adv. 6:4634–4644. 2022. View Article : Google Scholar :

Zheng L, Qin S, Si W, Wang A, Xing B, Gao R, Ren X, Wang L, Wu X, Zhang J, et al: Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science. 374:abe64742021. View Article : Google Scholar

Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, et al: TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 571:265–269. 2019. View Article : Google Scholar : PubMed/NCBI

Kim K, Park S, Park SY, Kim G, Park SM, Cho JW, Kim DH, Park YM, Koh YW, Kim HR, et al: Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome Med. 12:222020. View Article : Google Scholar :

Abdel-Hakeem MS, Manne S, Beltra JC, Stelekati E, Chen Z, Nzingha K, Ali MA, Johnson JL, Giles JR, Mathew D, et al: Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat Immunol. 22:1008–1019. 2021. View Article : Google Scholar :

Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, Drake AM, Chen Z, Sen DR, Kurachi M, et al: Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science. 354:1160–1165. 2016. View Article : Google Scholar

Gupta PK, Godec J, Wolski D, Adland E, Yates K, Pauken KE, Cosgrove C, Ledderose C, Junger WG, Robson SC, et al: CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog. 11:e10051772015. View Article : Google Scholar : PubMed/NCBI

Tinoco R, Neubert EN, Stairiker CJ, Henriquez ML and Bradley LM: PSGL-1 is a T cell intrinsic inhibitor that regulates effector and memory differentiation and responses during viral infection. Front Immunol. 12:6778242021. View Article : Google Scholar :

Tinoco R, Carrette F, Barraza ML, Otero DC, Magaña J, Bosenberg MW, Swain SL and Bradley LM: PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion. Immunity. 44:1190–1203. 2016. View Article : Google Scholar

Vignali PDA, DePeaux K, Watson MJ, Ye C, Ford BR, Lontos K, McGaa NK, Scharping NE, Menk AV, Robson SC, et al: Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat Immunol. 24:267–279. 2023. View Article : Google Scholar

Viramontes KM, Neubert EN, DeRogatis JM and Tinoco R: PD-1 immune checkpoint blockade and PSGL-1 inhibition synergize to reinvigorate exhausted T cells. Front Immunol. 13:8697682022. View Article : Google Scholar :

Moesta AK, Li XY and Smyth MJ: Targeting CD39 in cancer. Nat Rev Immunol. 20:739–755. 2020. View Article : Google Scholar : PubMed/NCBI

Tu E, McGlinchey K, Wang J, Martin P, Ching SL, Floc'h N, Kurasawa J, Starrett JH, Lazdun Y, Wetzel L, et al: Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC. JCI Insight. 7:e1428432022. View Article : Google Scholar : PubMed/NCBI

Ford BR and Poholek AC: Regulation and immunotherapeutic targeting of the epigenome in exhausted CD8 T cell responses. J Immunol. 210:869–879. 2023. View Article : Google Scholar

Franco F, Jaccard A, Romero P, Yu YR and Ho PC: Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab. 2:1001–1012. 2020. View Article : Google Scholar : PubMed/NCBI

Gabriel SS, Tsui C, Chisanga D, Weber F, Llano-León M, Gubser PM, Bartholin L, Souza-Fonseca-Guimaraes F, Huntington ND, Shi W, et al: Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection. Immunity. 54:1698–1714.e5. 2021. View Article : Google Scholar

Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM and Wherry EJ: Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity. 45:358–373. 2016. View Article : Google Scholar : PubMed/NCBI

Guo Y, Xie YQ, Gao M, Zhao Y, Franco F, Wenes M, Siddiqui I, Bevilacqua A, Wang H, Yang H, et al: Metabolic reprogramming of terminally exhausted CD8⁺ T cells by IL-10 enhances anti-tumor immunity. Nat Immunol. 22:746–756. 2021. View Article : Google Scholar :

Tsui C, Kretschmer L, Rapelius S, Gabriel SS, Chisanga D, Knöpper K, Utzschneider DT, Nüssing S, Liao Y, Mason T, et al: MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature. 609:354–360. 2022. View Article : Google Scholar :

Stelekati E, Chen Z, Manne S, Kurachi M, Ali MA, Lewy K, Cai Z, Nzingha K, McLane LM, Hope JL, et al: Long-term persistence of exhausted CD8 T cells in chronic infection is regulated by MicroRNA-155. Cell Rep. 23:2142–2156. 2018. View Article : Google Scholar : PubMed/NCBI

Utzschneider DT, Gabriel SS, Chisanga D, Gloury R, Gubser PM, Vasanthakumar A, Shi W and Kallies A: Early precursor T cells establish and propagate T cell exhaustion in chronic infection. Nat Immun. 21:1256–1266. 2020. View Article : Google Scholar

Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, Pellegrini M, Zehn D, Berberich-Siebelt F, Febbraio MA, et al: Transcription factor IRF4 promotes CD8⁺ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity. 47:1129–1141.e5. 2017. View Article : Google Scholar

Seo H, González-Avalos E, Zhang W, Ramchandani P, Yang C, Lio CJ, Rao A and Hogan PG: BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat Immunol. 22:983–995. 2021. View Article : Google Scholar :

Russ BE, Tsyganov K, Quon S, Yu B, Li J, Lee JKC, Olshansky M, He Z, Harrison PF, Barugahare A, et al: Active maintenance of CD8⁺ T cell naïvety through regulation of global genome architecture. bioRxiv: The preprint server for biology. 2023.

Grusdat M, McIlwain DR, Xu HC, Pozdeev VI, Knievel J, Crome SQ, Robert-Tissot C, Dress RJ, Pandyra AA, Speiser DE, et al: IRF4 and BATF are critical for CD8⁺ T-cell function following infection with LCMV. Cell Death Differ. 21:1050–1060. 2014. View Article : Google Scholar : PubMed/NCBI

Jain N, Zhao Z, Feucht J, Koche R, Iyer A, Dobrin A, Mansilla-Soto J, Yang J, Zhan Y, Lopez M, et al: TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature. 615:315–322. 2023. View Article : Google Scholar : PubMed/NCBI

Jordan MS, Drury S, Giles JR, Manne S, Huang H, Chen Z, Oldridge D, Wherry EJ and Baxter AE: TET2 controls differentiation of terminally exhausted CD8 T cells. J Immunol. 206(1 Suppl): S14.072021. View Article : Google Scholar

Liu B, Hu X, Feng K, Gao R, Xue Z, Zhang S, Zhang Y, Corse E, Hu Y, Han W and Zhang Z: Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer. Nat Cancer. 3:108–121. 2022. View Article : Google Scholar

Luoma AM, Suo S, Wang Y, Gunasti L, Porter CBM, Nabilsi N, Tadros J, Ferretti AP, Liao S, Gurer C, et al: Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell. 185:2918–2935.e29. 2022. View Article : Google Scholar : PubMed/NCBI

Li Z, Tuong ZK, Dean I, Willis C, Gaspal F, Fiancette R, Idris S, Kennedy B, Ferdinand JR, Peñalver A, et al: In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue. J Exp Med. 219:e202107492022. View Article : Google Scholar : PubMed/NCBI

Kennedy BC, Dean I and Withers DR: Migration of stem-like CD8 T cells between tissue microenvironments underpins successful anti-tumour immune responses. Discov Immunol. 2:kyad0042023. View Article : Google Scholar : PubMed/NCBI

Fransen MF, Schoonderwoerd M, Knopf P, Camps MG, Hawinkels LJ, Kneilling M, van Hall T and Ossendorp F: Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy. JCI Insight. 3:e1245072018. View Article : Google Scholar : PubMed/NCBI

Liu Z, Yu Z, Chen D, Verma V, Yuan C, Wang M, Wang F, Fan Q, Wang X, Li Y, et al: Pivotal roles of tumor-draining lymph nodes in the abscopal effects from combined immunotherapy and radiotherapy. Cancer Commun (Lond). 42:971–986. 2022. View Article : Google Scholar : PubMed/NCBI

Tanaka R, Hiramitsu M, Shimizu S, Kawashima S, Sato A and Iwase Y: Efficient drug delivery to lymph nodes by intradermal administration and enhancement of anti-tumor effects of immune checkpoint inhibitors. Cancer Treat Res Commun. 36:1007402023. View Article : Google Scholar : PubMed/NCBI

du Bois H, Heim TA and Lund AW: Tumor-draining lymph nodes: At the crossroads of metastasis and immunity. Sci Immunol. 6:eabg35512021. View Article : Google Scholar : PubMed/NCBI

Rahim MK, Okholm TLH, Jones KB, McCarthy EE, Liu CC, Yee JL, Ki SJ, Marquez DM, Tenvooren I, Wai K, et al: Dynamic CD8⁺ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell. 186:1127–1143.e18. 2023. View Article : Google Scholar

Buchwald ZS, Nasti TH, Lee J, Eberhardt CS, Wieland A, Im SJ, Lawson D, Curran W, Ahmed R and Khan MK: Tumor-draining lymph node is important for a robust abscopal effect stimulated by radiotherapy. J Immunother Cancer. 8:e0008672020. View Article : Google Scholar : PubMed/NCBI

Fear VS, Forbes CA, Neeve SA, Fisher SA, Chee J, Waithman J, Ma SK, Lake R, Nowak AK, Creaney J, et al: Tumour draining lymph node-generated CD8 T cells play a role in controlling lung metastases after a primary tumour is removed but not when adjuvant immunotherapy is used. Cancer Immunol Immunother. 70:3249–3258. 2021. View Article : Google Scholar : PubMed/NCBI

Dammeijer F, van Gulijk M, Mulder EE, Lukkes M, Klaase L, van den Bosch T, van Nimwegen M, Lau SP, Latupeirissa K, Schetters S, et al: The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell. 38:685–700.e8. 2020. View Article : Google Scholar

Zhou Y, Slone N, Chrisikos TT, Kyrysyuk O, Babcock RL, Medik YB, Li HS, Kleinerman ES and Watowich SS: Vaccine efficacy against primary and metastatic cancer with in vitro-generated CD103⁺ conventional dendritic cells. J Immunother Cancer. 8:e0004742020. View Article : Google Scholar

Salmon H, Idoyaga J, Rahman A, Leboeuf M, Remark R, Jordan S, Casanova-Acebes M, Khudoynazarova M, Agudo J, Tung N, et al: Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition. Immunity. 44:924–938. 2016. View Article : Google Scholar : PubMed/NCBI

Huang Q, Wu X, Wang Z, Chen X, Wang L, Lu Y, Xiong D, Liu Q, Tian Y, Lin H, et al: The primordial differentiation of tumor-specific memory CD8⁺ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell. 185:4049–4066.e25. 2022. View Article : Google Scholar

Okamura K, Nagayama S, Tate T, Chan HT, Kiyotani K and Nakamura Y: Lymphocytes in tumor-draining lymph nodes co-cultured with autologous tumor cells for adoptive cell therapy. J Transl Med. 20:2412022. View Article : Google Scholar : PubMed/NCBI

Schenkel JM, Herbst RH, Canner D, Li A, Hillman M, Shanahan SL, Gibbons G, Smith OC, Kim JY, Westcott P, et al: Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1⁺ CD8⁺ T cells in tumor-draining lymph nodes. Immunity. 54:2338–2353.e6. 2021. View Article : Google Scholar

Connolly KA, Kuchroo M, Venkat A, Khatun A, Wang J, William I, Hornick NI, Fitzgerald BL, Damo M, Kasmani MY, et al: A reservoir of stem-like CD8⁺ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci Immunol. 6:eabg78362021. View Article : Google Scholar

O'Melia MJ, Manspeaker MP and Thomas SN: Tumor-draining lymph nodes are survival niches that support T cell priming against lymphatic transported tumor antigen and effects of immune checkpoint blockade in TNBC. Cancer Immunol Immunother. 70:2179–2195. 2021. View Article : Google Scholar : PubMed/NCBI

Dominguez-Gutierrez PR, Kwenda EP, Donelan W, Miranda M, Doty A, O'Malley P, Crispen PL and Kusmartsev S: Detection of PD-L1-expressing myeloid cell clusters in the hyaluronan-enriched stroma in tumor tissue and tumor-draining lymph nodes. J Immunol. 208:2829–2836. 2022. View Article : Google Scholar : PubMed/NCBI

Núñez NG, Tosello Boari J, Ramos RN, Richer W, Cagnard N, Anderfuhren CD, Niborski LL, Bigot J, Meseure D, De La Rochere P, et al: Tumor invasion in draining lymph nodes is associated with Treg accumulation in breast cancer patients. Nat Commun. 11:32722020. View Article : Google Scholar : PubMed/NCBI

Yang H, Sun B, Ma W, Fan L, Xu K, Jia Y, Xu J, Wang Z and Yao F: Multi-scale characterization of tumor-draining lymph nodes in resectable lung cancer treated with neoadjuvant immune checkpoint inhibitors. EBioMedicine. 84:1042652022. View Article : Google Scholar : PubMed/NCBI

Schumacher TN and Thommen DS: Tertiary lymphoid structures in cancer. Science. 375:eabf94192022. View Article : Google Scholar : PubMed/NCBI

Dieu-Nosjean MC, Giraldo NA, Kaplon H, Germain C, Fridman WH and Sautès-Fridman C: Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers. Immunol Rev. 271:260–275. 2016. View Article : Google Scholar : PubMed/NCBI

Rodriguez AB, Peske JD, Woods AN, Leick KM, Mauldin IS, Meneveau MO, Young SJ, Lindsay RS, Melssen MM, Cyranowski S, et al: Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts. Cell Rep. 36:1094222021. View Article : Google Scholar : PubMed/NCBI

Ng KW, Boumelha J, Enfield KSS, Almagro J, Cha H, Pich O, Karasaki T, Moore DA, Salgado R, Sivakumar M, et al: Antibodies against endogenous retroviruses promote lung cancer immunotherapy. Nature. 616:563–573. 2023. View Article : Google Scholar : PubMed/NCBI

Wang B, Liu J, Han Y, Deng Y, Li J and Jiang Y: The presence of tertiary lymphoid structures provides new insight into the clinicopathological features and prognosis of patients with breast cancer. Front Immunol. 13:8681552022. View Article : Google Scholar : PubMed/NCBI

Wang Q, Shen X, An R, Bai J, Dong J, Cai H, Zhu H, Zhong W, Chen W, Liu A and Du J: Peritumoral tertiary lymphoid structure and tumor stroma percentage predict the prognosis of patients with non-metastatic colorectal cancer. Front Immunol. 13:9620562022. View Article : Google Scholar : PubMed/NCBI

Zhang WH, Wang WQ, Han X, Gao HL, Xu SS, Li S, Li TJ, Xu HX, Li H, Ye LY, et al: Infiltrating pattern and prognostic value of tertiary lymphoid structures in resected non-functional pancreatic neuroendocrine tumors. J Immunother Cancer. 8:e0011882020. View Article : Google Scholar : PubMed/NCBI

Tanaka T, Masuda A, Inoue J, Hamada T, Ikegawa T, Toyama H, Sofue K, Shiomi H, Sakai A, Kobayashi T, et al: Integrated analysis of tertiary lymphoid structures in relation to tumor-infiltrating lymphocytes and patient survival in pancreatic ductal adenocarcinoma. J Gastroenterol. 58:277–291. 2023. View Article : Google Scholar : PubMed/NCBI

Ukita M, Hamanishi J, Yoshitomi H, Yamanoi K, Takamatsu S, Ueda A, Suzuki H, Hosoe Y, Furutake Y, Taki M, et al: CXCL13-producing CD4+ T cells accumulate in the early phase of tertiary lymphoid structures in ovarian cancer. JCI Insight. 7:e1572152022. View Article : Google Scholar : PubMed/NCBI

Siliņa K, Soltermann A, Attar FM, Casanova R, Uckeley ZM, Thut H, Wandres M, Isajevs S, Cheng P, Curioni-Fontecedro A, et al: Germinal centers determine the prognostic relevance of tertiary lymphoid structures and are impaired by corticosteroids in lung squamous cell carcinoma. Cancer Res. 78:1308–1320. 2018. View Article : Google Scholar

Yang M, Lu J, Zhang G, Wang Y, He M, Xu Q, Xu C and Liu H: CXCL13 shapes immunoactive tumor microenvironment and enhances the efficacy of PD-1 checkpoint blockade in high-grade serous ovarian cancer. J Immunother Cancer. 9:e0011362021. View Article : Google Scholar : PubMed/NCBI

Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, Johansson I, Phung B, Harbst K, Vallon-Christersson J, et al: Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 577:561–565. 2020. View Article : Google Scholar : PubMed/NCBI

Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, Yizhak K, Sade-Feldman M, Blando J, Han G, et al: B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 577:549–555. 2020. View Article : Google Scholar : PubMed/NCBI

Petitprez F, de Reyniès A, Keung EZ, Chen TW, Sun CM, Calderaro J, Jeng YM, Hsiao LP, Lacroix L, Bougoüin A, et al: B cells are associated with survival and immunotherapy response in sarcoma. Nature. 577:556–560. 2020. View Article : Google Scholar : PubMed/NCBI

Sawada J, Hiraoka N, Qi R, Jiang L, Fournier-Goss AE, Yoshida M, Kawashima H and Komatsu M: Molecular signature of tumor-associated high endothelial venules that can predict breast cancer survival. Cancer Immunol Res. 10:468–481. 2022. View Article : Google Scholar : PubMed/NCBI

Martinet L, Garrido I, Filleron T, Le Guellec S, Bellard E, Fournie JJ, Rochaix P and Girard JP: Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer. Cancer Res. 71:5678–5687. 2011. View Article : Google Scholar : PubMed/NCBI

Asrir A, Tardiveau C, Coudert J, Laffont R, Blanchard L, Bellard E, Veerman K, Bettini S, Lafouresse F, Vina E, et al: Tumor-associated high endothelial venules mediate lymphocyte entry into tumors and predict response to PD-1 plus CTLA-4 combination immunotherapy. Cancer Cell. 40:318–334.e9. 2022. View Article : Google Scholar : PubMed/NCBI

Li Z, Jiang Y, Li B, Han Z, Shen J, Xia Y and Li R: Development and validation of a machine learning model for detection and classification of tertiary lymphoid structures in gastrointestinal cancers. JAMA Netw Open. 6:e22525532023. View Article : Google Scholar : PubMed/NCBI

Neyt K, Perros F, GeurtsvanKessel CH, Hammad H and Lambrecht BN: Tertiary lymphoid organs in infection and autoimmunity. Trends Immunol. 33:297–305. 2012. View Article : Google Scholar : PubMed/NCBI

Hayashi Y, Makino T, Sato E, Ohshima K, Nogi Y, Kanemura T, Honma K, Yamashita K, Saito T, Tanaka K, et al: Density and maturity of peritumoral tertiary lymphoid structures in oesophageal squamous cell carcinoma predicts patient survival and response to immune checkpoint inhibitors. Br J Cancer. 128:2175–2185. 2023. View Article : Google Scholar : PubMed/NCBI

Deguchi S, Tanaka H, Suzuki S, Natsuki S, Mori T, Miki Y, Yoshii M, Tamura T, Toyokawa T, Lee S, et al: Clinical relevance of tertiary lymphoid structures in esophageal squamous cell carcinoma. BMC Cancer. 22:6992022. View Article : Google Scholar : PubMed/NCBI

Ling Y, Zhong J, Weng Z, Lin G, Liu C, Pan C, Yang H, Wei X, Xie X, Wei X, et al: The prognostic value and molecular properties of tertiary lymphoid structures in oesophageal squamous cell carcinoma. Clin Transl Med. 12:e10742022. View Article : Google Scholar : PubMed/NCBI

Calderaro J, Petitprez F, Becht E, Laurent A, Hirsch TZ, Rousseau B, Luciani A, Amaddeo G, Derman J, Charpy C, et al: Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. J Hepatol. 70:58–65. 2019. View Article : Google Scholar

Sun X, Liu W, Sun L, Mo H, Feng Y, Wu X, Li C, Chen C, Li J, Xin Y, et al: Maturation and abundance of tertiary lymphoid structures are associated with the efficacy of neoadjuvant chemoimmunotherapy in resectable non-small cell lung cancer. J Immunother Cancer. 10:e0055312022. View Article : Google Scholar :

Lynch KT, Young SJ, Meneveau MO, Wages NA, Engelhard VH, Slingluff CL Jr and Mauldin IS: Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma. J Immunother Cancer. 9:e0022732021. View Article : Google Scholar : PubMed/NCBI

Posch F, Silina K, Leibl S, Mündlein A, Moch H, Siebenhüner A, Samaras P, Riedl J, Stotz M, Szkandera J, et al: Maturation of tertiary lymphoid structures and recurrence of stage II and III colorectal cancer. Oncoimmunology. 7:e13788442017. View Article : Google Scholar

Zhang Q and Wu S: Tertiary lymphoid structures are critical for cancer prognosis and therapeutic response. Front Immunol. 13:10637112023. View Article : Google Scholar : PubMed/NCBI

Fridman WH, Meylan M, Petitprez F, Sun CM, Italiano A and Sautès-Fridman C: B cells and tertiary lymphoid structures as determinants of tumour immune contexture and clinical outcome. Nat Rev Clin Oncol. 19:441–457. 2022. View Article : Google Scholar : PubMed/NCBI

Saito T, Nishikawa H, Wada H, Nagano Y, Sugiyama D, Atarashi K, Maeda Y, Hamaguchi M, Ohkura N, Sato E, et al: Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. 22:679–684. 2016. View Article : Google Scholar : PubMed/NCBI

Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D, Willimsky G, Ammirante M, Strasner A, Hansel DE, et al: Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature. 521:94–98. 2015. View Article : Google Scholar : PubMed/NCBI

Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, Browning JL, Goossens N, Nakagawa S, Gunasekaran G, et al: Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 16:1235–1244. 2015. View Article : Google Scholar : PubMed/NCBI

Milutinovic S, Abe J, Godkin A, Stein JV and Gallimore A: The dual role of high endothelial venules in cancer progression versus immunity. Trends Cancer. 7:214–225. 2021. View Article : Google Scholar

Sautès-Fridman C, Petitprez F, Calderaro J and Fridman WH: Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 19:307–325. 2019. View Article : Google Scholar : PubMed/NCBI

Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I, Tredan O, Verweij J, Biron P, Labidi I, et al: Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 69:5383–5391. 2009. View Article : Google Scholar : PubMed/NCBI

Wu Z, Zhang J, Cai Y, Deng R, Yang L, Li J and Deng Y: Reduction of circulating lymphocyte count is a predictor of good tumor response after neoadjuvant treatment for rectal cancer. Medicine (Baltimore). 97:e114352018. View Article : Google Scholar : PubMed/NCBI

Lee YJ, Park YS, Lee HW, Park TY, Lee JK and Heo EY: Peripheral lymphocyte count as a surrogate marker of immune checkpoint inhibitor therapy outcomes in patients with non-small-cell lung cancer. Sci Rep. 12:6262022. View Article : Google Scholar : PubMed/NCBI

Weide B, Martens A, Hassel JC, Berking C, Postow MA, Bisschop K, Simeone E, Mangana J, Schilling B, Di Giacomo AM, et al: Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab. Clin Cancer Res. 22:5487–5496. 2016. View Article : Google Scholar : PubMed/NCBI

Martens A, Wistuba-Hamprecht K, Geukes Foppen M, Yuan J, Postow MA, Wong P, Romano E, Khammari A, Dreno B, Capone M, et al: Baseline peripheral blood biomarkers associated with clinical outcome of advanced melanoma patients treated with ipilimumab. Clin Cancer Res. 22:2908–2918. 2016. View Article : Google Scholar : PubMed/NCBI

Juliá EP, Mandó P, Rizzo MM, Cueto GR, Tsou F, Luca R, Pupareli C, Bravo AI, Astorino W, Mordoh J, et al: Peripheral changes in immune cell populations and soluble mediators after anti-PD-1 therapy in non-small cell lung cancer and renal cell carcinoma patients. Cancer Immunol Immunother. 68:1585–1596. 2019. View Article : Google Scholar : PubMed/NCBI

Cui JH, Lin KR, Yuan SH, Jin YB, Chen XP, Su XK, Jiang J, Pan YM, Mao SL, Mao XF and Luo W: TCR repertoire as a novel indicator for immune monitoring and prognosis assessment of patients with cervical cancer. Front Immunol. 9:27292018. View Article : Google Scholar : PubMed/NCBI

Gleason L, Porcu P and Nikbakht N: Reduced overall T-cell receptor diversity as an indicator of aggressive cutaneous T-cell lymphoma. Blood. 140(Suppl 1): 3539–3540. 2022. View Article : Google Scholar

Manuel M, Tredan O, Bachelot T, Clapisson G, Courtier A, Parmentier G, Rabeony T, Grives A, Perez S, Mouret JF, et al: Lymphopenia combined with low TCR diversity (divpenia) predicts poor overall survival in metastatic breast cancer patients. Oncoimmunology. 1:432–440. 2012. View Article : Google Scholar : PubMed/NCBI

Lin KR, Pang DM, Jin YB, Hu Q, Pan YM, Cui JH, Chen XP, Lin YX, Mao XF, Duan HB and Luo W: Circulating CD8⁺ T-cell repertoires reveal the biological characteristics of tumors and clinical responses to chemotherapy in breast cancer patients. Cancer Immunol Immunother. 67:1743–1752. 2018. View Article : Google Scholar : PubMed/NCBI

Cai G, Guan Z, Jin Y, Su Z, Chen X, Liu Q, Wang C, Yin X, Zhang L, Ye G and Luo W: Circulating T-cell repertoires correlate with the tumor response in patients with breast cancer receiving neoadjuvant chemotherapy. JCO Precis Oncol. 6:e21001202022. View Article : Google Scholar : PubMed/NCBI

Page DB, Yuan J, Redmond D, Wen YH, Durack JC, Emerson R, Solomon S, Dong Z, Wong P, Comstock C, et al: Deep sequencing of T-cell receptor DNA as a biomarker of clonally expanded TILs in breast cancer after immunotherapy. Cancer Immunol Res. 4:835–844. 2016. View Article : Google Scholar : PubMed/NCBI

Kuehm LM, Wolf K, Zahour J, DiPaolo RJ and Teague RM: Checkpoint blockade immunotherapy enhances the frequency and effector function of murine tumor-infiltrating T cells but does not alter TCRβ diversity. Cancer Immunol Immunother. 68:1095–1106. 2019. View Article : Google Scholar : PubMed/NCBI

Rudqvist NP, Pilones KA, Lhuillier C, Wennerberg E, Sidhom JW, Emerson RO, Robins HS, Schneck J, Formenti SC and Demaria S: Radiotherapy and CTLA-4 blockade shape the TCR repertoire of tumor-infiltrating T cells. Cancer Immunol Res. 6:139–150. 2018. View Article : Google Scholar :

Wu TD, Madireddi S, de Almeida PE, Banchereau R, Chen YJ, Chitre AS, Chiang EY, Iftikhar H, O'Gorman WE, Au-Yeung A, et al: Peripheral T cell expansion predicts tumour infiltration and clinical response. Nature. 579:274–278. 2020. View Article : Google Scholar : PubMed/NCBI

Puig-Saus C, Sennino B, Peng S, Wang CL, Pan Z, Yuen B, Purandare B, An D, Quach BB, Nguyen D, et al: Neoantigen-targeted CD8⁺ T cell responses with PD-1 blockade therapy. Nature. 615:697–704. 2023. View Article : Google Scholar : PubMed/NCBI

Dong N, Moreno-Manuel A, Calabuig-Fariñas S, Gallach S, Zhang F, Blasco A, Aparisi F, Meri-Abad M, Guijarro R, Sirera R, et al: Characterization of circulating T cell receptor repertoire provides information about clinical outcome after PD-1 blockade in advanced non-small cell lung cancer patients. Cancers (Basel). 13:29502021. View Article : Google Scholar : PubMed/NCBI

Han J, Duan J, Bai H, Wang Y, Wan R, Wang X, Chen S, Tian Y, Wang D, Fei K, et al: TCR repertoire diversity of peripheral PD-1⁺CD8⁺ T cells predicts clinical outcomes after immunotherapy in patients with non-small lung cancer. Cancer Immunol Res. 8:146–154. 2020. View Article : Google Scholar

Kato T, Kiyotani K, Tomiyama E, Koh Y, Matsushita M, Hayashi Y, Nakano K, Ishizuya Y, Wang C, Hatano K, et al: Peripheral T cell receptor repertoire features predict durable responses to anti-PD-1 inhibitor monotherapy in advanced renal cell carcinoma. Oncoimmunology. 10:18629482021. View Article : Google Scholar : PubMed/NCBI

Snyder A, Nathanson T, Funt SA, Ahuja A, Buros Novik J, Hellmann MD, Chang E, Aksoy BA, Al-Ahmadie H, Yusko E, et al: Contribution of systemic and somatic factors to clinical response and resistance to PD-L1 blockade in urothelial cancer: An exploratory multi-omic analysis. PLoS Med. 14:e10023092017. View Article : Google Scholar : PubMed/NCBI

Arakawa A, Vollmer S, Tietze J, Galinski A, Heppt MV, Bürdek M, Berking C and Prinz JC: Clonality of CD4⁺ blood T cells predicts longer survival with CTLA4 or PD-1 checkpoint inhibition in advanced melanoma. Front Immunol. 10:13362019. View Article : Google Scholar

Zhu Q, Qiao G, Huang L, Xu C, Guo D, Wang S, Zhao J, Song Y, Liu B, Chen Z, et al: Restored CD8⁺PD-1⁺ T cells facilitate the response to Anti-PD-1 for patients with pancreatic ductal adenocarcinoma. Front Oncol. 12:8375602022. View Article : Google Scholar

Verronèse E, Delgado A, Valladeau-Guilemond J, Garin G, Guillemaut S, Tredan O, Ray-Coquard I, Bachelot T, N'Kodia A, Bardin-Dit-Courageot C, et al: Immune cell dysfunctions in breast cancer patients detected through whole blood multi-parametric flow cytometry assay. Oncoimmunology. 5:e11007912015. View Article : Google Scholar

Saleh R and Elkord E: FoxP3⁺ T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett. 490:174–185. 2020. View Article : Google Scholar : PubMed/NCBI

Sakaguchi S, Miyara M, Costantino CM and Hafler DA: FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 10:490–500. 2010. View Article : Google Scholar : PubMed/NCBI

Kotsakis A, Koinis F, Katsarou A, Gioulbasani M, Aggouraki D, Kentepozidis N, Georgoulias V and Vetsika EK: Prognostic value of circulating regulatory T cell subsets in untreated non-small cell lung cancer patients. Sci Rep. 6:392472016. View Article : Google Scholar : PubMed/NCBI

Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Gonçalves A, André P, Romagné F, Thibault G, et al: Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest. 121:3609–3622. 2011. View Article : Google Scholar : PubMed/NCBI

Manjarrez-Orduño N, Menard LC, Kansal S, Fischer P, Kakrecha B, Jiang C, Cunningham M, Greenawalt D, Patel V, Yang M, et al: Circulating T cell subpopulations correlate with immune responses at the tumor site and clinical response to PD1 inhibition in non-small cell lung cancer. Front Immunol. 9:16132018. View Article : Google Scholar : PubMed/NCBI

Kim CG, Kim KH, Pyo KH, Xin CF, Hong MH, Ahn BC, Kim Y, Choi SJ, Yoon HI, Lee JG, et al: Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol. 30:1104–1113. 2019. View Article : Google Scholar : PubMed/NCBI

Wistuba-Hamprecht K, Martens A, Heubach F, Romano E, Geukes Foppen M, Yuan J, Postow M, Wong P, Mallardo D, Schilling B, et al: Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients. Eur J Cancer. 73:61–70. 2017. View Article : Google Scholar : PubMed/NCBI

Kagamu H, Kitano S, Yamaguchi O, Yoshimura K, Horimoto K, Kitazawa M, Fukui K, Shiono A, Mouri A, Nishihara F, et al: CD4⁺ T-cell Immunity in the peripheral blood correlates with response to Anti-PD-1 therapy. Cancer Immunol Res. 8:334–344. 2020. View Article : Google Scholar

Sade-Feldman M, Kanterman J, Klieger Y, Ish-Shalom E, Olga M, Saragovi A, Shtainberg H, Lotem M and Baniyash M: Clinical significance of circulating CD33+CD11b+HLA-DR-myeloid cells in patients with stage IV melanoma treated with ipilimumab. Clin Cancer Res. 22:5661–5672. 2016. View Article : Google Scholar : PubMed/NCBI

Zuazo M, Arasanz H, Fernández-Hinojal G, García-Granda MJ, Gato M, Bocanegra A, Martínez M, Hernández B, Teijeira L, Morilla I, et al: Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy. EMBO Mol Med. 11:e102932019. View Article : Google Scholar : PubMed/NCBI

Mazzaschi G, Facchinetti F, Missale G, Canetti D, Madeddu D, Zecca A, Veneziani M, Gelsomino F, Goldoni M, Buti S, et al: The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC. Lung Cancer. 127:153–163. 2019. View Article : Google Scholar : PubMed/NCBI

Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, et al: PD-1⁺ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Proc Natl Acad Sci USA. 116:9999–10008. 2019. View Article : Google Scholar

Jacquelot N, Roberti MP, Enot DP, Rusakiewicz S, Ternès N, Jegou S, Woods DM, Sodré AL, Hansen M, Meirow Y, et al: Predictors of responses to immune checkpoint blockade in advanced melanoma. Nat Commun. 8:5922017. View Article : Google Scholar : PubMed/NCBI

Ferrara R, Naigeon M, Auclin E, Duchemann B, Cassard L, Jouniaux JM, Boselli L, Grivel J, Desnoyer A, Mezquita L, et al: Circulating T-cell immunosenescence in patients with advanced non-small cell lung cancer treated with single-agent PD-1/PD-L1 inhibitors or platinum-based chemotherapy. Clin Cancer Res. 27:492–503. 2021. View Article : Google Scholar

Griffiths JI, Wallet P, Pflieger LT, Stenehjem D, Liu X, Cosgrove PA, Leggett NA, McQuerry JA, Shrestha G, Rossetti M, et al: Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy. Proc Natl Acad Sci USA. 117:16072–16082. 2020. View Article : Google Scholar : PubMed/NCBI

Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch B, Manne S, Xu W, Harmon S, Giles JR, Wenz B, et al: T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature. 545:60–65. 2017. View Article : Google Scholar : PubMed/NCBI

Kwon M, An M, Klempner SJ, Lee H, Kim KM, Sa JK, Cho HJ, Hong JY, Lee T, Min YW, et al: Determinants of response and intrinsic resistance to PD-1 blockade in microsatellite instability-high gastric cancer. Cancer Discov. 11:2168–2185. 2021. View Article : Google Scholar : PubMed/NCBI

Kamphorst AO, Pillai RN, Yang S, Nasti TH, Akondy RS, Wieland A, Sica GL, Yu K, Koenig L, Patel NT, et al: Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci USA. 114:4993–4998. 2017. View Article : Google Scholar : PubMed/NCBI

Kim KH, Cho J, Ku BM, Koh J, Sun JM, Lee SH, Ahn JS, Cheon J, Min YJ, Park SH, et al: The first-week proliferative response of peripheral blood PD-1⁺CD8⁺ T cells predicts the response to anti-PD-1 therapy in solid tumors. Clin Cancer Res. 25:2144–2154. 2019. View Article : Google Scholar : PubMed/NCBI

Krieg C, Nowicka M, Guglietta S, Schindler S, Hartmann FJ, Weber LM, Dummer R, Robinson MD, Levesque MP and Becher B: High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nat Med. 24:144–153. 2018. View Article : Google Scholar : PubMed/NCBI

de Coaña YP, Wolodarski M, Poschke I, Yoshimoto Y, Yang Y, Nyström M, Edbäck U, Brage SE, Lundqvist A, Masucci GV, et al: Ipilimumab treatment decreases monocytic MDSCs and increases CD8 effector memory T cells in long-term survivors with advanced melanoma. Oncotarget. 8:21539–21553. 2017. View Article : Google Scholar : PubMed/NCBI

Duchemann B, Naigeon M, Auclin E, Ferrara R, Cassard L, Jouniaux JM, Boselli L, Grivel J, Desnoyer A, Danlos FX, et al: CD8⁺PD-1⁺ to CD4⁺PD-1⁺ ratio (PERLS) is associated with prognosis of patients with advanced NSCLC treated with PD-(L)1 blockers. J Immunother Cancer. 10:e0040122022. View Article : Google Scholar

Youn JI, Park SM, Park S, Kim G, Lee HJ, Son J, Hong MH, Ghaderpour A, Baik B, Islam J, et al: Peripheral natural killer cells and myeloid-derived suppressor cells correlate with anti-PD-1 responses in non-small cell lung cancer. Sci Rep. 10:90502020. View Article : Google Scholar : PubMed/NCBI

Dodagatta-Marri E, Meyer DS, Reeves MQ, Paniagua R, To MD, Binnewies M, Broz ML, Mori H, Wu D, Adoumie M, et al: α-PD-1 therapy elevates Treg/Th balance and increases tumor cell pSmad3 that are both targeted by α-TGFβ antibody to promote durable rejection and immunity in squamous cell carcinomas. J Immunother Cancer. 7:622019. View Article : Google Scholar

Takeuchi Y, Tanemura A, Tada Y, Katayama I, Kumanogoh A and Nishikawa H: Clinical response to PD-1 blockade correlates with a sub-fraction of peripheral central memory CD4+ T cells in patients with malignant melanoma. Int Immunol. 30:13–22. 2018. View Article : Google Scholar : PubMed/NCBI

Kato R, Yamasaki M, Urakawa S, Nishida K, Makino T, Morimoto-Okazawa A, Kawashima A, Iwahori K, Suzuki S, Ueda R, et al: Increased Tim-3⁺ T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients. Cancer Immunol Immunother. 67:1673–1683. 2018. View Article : Google Scholar : PubMed/NCBI

Sangro B, Melero I, Wadhawan S, Finn RS, Abou-Alfa GK, Cheng AL, Yau T, Furuse J, Park JW, Boyd Z, et al: Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol. 73:1460–1469. 2020. View Article : Google Scholar : PubMed/NCBI

Kim HR, Park SM, Seo SU, Jung I, Yoon HI, Gabrilovich DI, Cho BC, Seong SY, Ha SJ and Youn JI: The ratio of peripheral regulatory T cells to Lox-1⁺ polymorphonuclear myeloid-derived suppressor cells predicts the early response to Anti-PD-1 therapy in patients with non-small cell lung cancer. Am J Respir Crit Care Med. 199:243–246. 2019. View Article : Google Scholar :

Jia XH, Geng LY, Jiang PP, Xu H, Nan KJ, Yao Y, Jiang LL, Sun H, Qin TJ and Guo H: The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors. J Exp Clin Cancer Res. 39:2842020. View Article : Google Scholar : PubMed/NCBI

Schweizer C, Schubert P, Rutzner S, Eckstein M, Haderlein M, Lettmaier S, Semrau S, Gostian AO, Frey B, Gaipl US, et al: Prospective evaluation of the prognostic value of immune-related adverse events in patients with non-melanoma solid tumour treated with PD-1/PD-L1 inhibitors alone and in combination with radiotherapy. Eur J Cancer. 140:55–62. 2020. View Article : Google Scholar : PubMed/NCBI

Chuah S, Lee J, Song Y, Kim HD, Wasser M, Kaya NA, Bang K, Lee YJ, Jeon SH, Suthen S, et al: Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma. J Hepatol. 77:683–694. 2022. View Article : Google Scholar : PubMed/NCBI

Zhu H, Galdos FX, Lee D, Waliany S, Huang YV, Ryan J, Dang K, Neal JW, Wakelee HA, Reddy SA, et al: Identification of pathogenic immune cell subsets associated with checkpoint inhibitor-induced myocarditis. Circulation. 146:316–335. 2022. View Article : Google Scholar : PubMed/NCBI

Franken A, Van Mol P, Vanmassenhove S, Donders E, Schepers R, Van Brussel T, Dooms C, Yserbyt J, De Crem N, Testelmans D, et al: Single-cell transcriptomics identifies pathogenic T-helper 17.1 cells and pro-inflammatory monocytes in immune checkpoint inhibitor-related pneumonitis. J Immunother Cancer. 10:e0053232022. View Article : Google Scholar : PubMed/NCBI

Kim KH, Hur JY, Cho J, Ku BM, Koh J, Koh JY, Sun JM, Lee SH, Ahn JS, Park K, et al: Immune-related adverse events are clustered into distinct subtypes by T-cell profiling before and early after anti-PD-1 treatment. Oncoimmunology. 9:17220232020. View Article : Google Scholar : PubMed/NCBI

Wei SC, Meijers WC, Axelrod ML, Anang NAAS, Screever EM, Wescott EC, Johnson DB, Whitley E, Lehmann L, Courand PY, et al: A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention. Cancer Discov. 11:614–625. 2021. View Article : Google Scholar :

Fairfax BP, Taylor CA, Watson RA, Nassiri I, Danielli S, Fang H, Mahé EA, Cooper R, Woodcock V, Traill Z, et al: Peripheral CD8⁺ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma. Nat Med. 26:193–199. 2020. View Article : Google Scholar : PubMed/NCBI

Chia S, Bedard PL, Hilton J, Amir E, Gelmon K, Goodwin R, Villa D, Cabanero M, Tu D, Tsao M and Seymour L: A phase Ib trial of durvalumab in combination with trastuzumab in HER2-positive metastatic breast cancer (CCTG IND.229). Oncologist. 24:1439–1445. 2019. View Article : Google Scholar : PubMed/NCBI

Soler MF, Abaurrea A, Azcoaga P, Araujo AM and Caffarel MM: New perspectives in cancer immunotherapy: Targeting IL-6 cytokine family. J Immunother Cancer. 11:e0075302023. View Article : Google Scholar : PubMed/NCBI

Wattenberg MM and Beatty GL: Overcoming immunotherapeutic resistance by targeting the cancer inflammation cycle. Semin Cancer Biol. 65:38–50. 2020. View Article : Google Scholar : PubMed/NCBI

Tobias J, Steinberger P, Drinić M and Wiedermann U: Emerging targets for anticancer vaccination: PD-1. ESMO Open. 6:1002782021. View Article : Google Scholar : PubMed/NCBI

Tang Q, Chen Y, Li X, Long S, Shi Y, Yu Y, Wu W, Han L and Wang S: The role of PD-1/PD-L1 and application of immune-checkpoint inhibitors in human cancers. Front Immunol. 13:9644422022. View Article : Google Scholar : PubMed/NCBI

Yang Y, Yu Y and Lu S: Effectiveness of PD-1/PD-L1 inhibitors in the treatment of lung cancer: Brightness and challenge. Sci China Life Sci. 63:1499–1514. 2020. View Article : Google Scholar : PubMed/NCBI

Reck M, Remon J and Hellmann MD: First-line immunotherapy for non-small-cell lung cancer. J Clin Oncol. 40:586–597. 2022. View Article : Google Scholar : PubMed/NCBI

Schoenfeld AJ, Arbour KC, Rizvi H, Iqbal AN, Gadgeel SM, Girshman J, Kris MG, Riely GJ, Yu HA and Hellmann MD: Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 30:839–844. 2019. View Article : Google Scholar : PubMed/NCBI

Kennedy LB and Salama AKS: A review of cancer immunotherapy toxicity. CA Cancer J Clin. 70:86–104. 2020. View Article : Google Scholar : PubMed/NCBI

Yi M, Zheng X, Niu M, Zhu S, Ge H and Wu K: Combination strategies with PD-1/PD-L1 blockade: Current advances and future directions. Mol Cancer. 21:282022. View Article : Google Scholar : PubMed/NCBI

Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, Izzeddine H, Marabelle A, Champiat S, Berdelou A, et al: Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 13:473–486. 2016. View Article : Google Scholar : PubMed/NCBI

Jhawar SR, Wang SJ, Thandoni A, Bommareddy PK, Newman JH, Marzo AL, Kuzel TM, Gupta V, Reiser J, Daniels P, et al: Combination oncolytic virus, radiation therapy, and immune checkpoint inhibitor treatment in anti-PD-1-refractory cancer. J Immunother Cancer. 11:e0067802023. View Article : Google Scholar : PubMed/NCBI

Gebrael G, Sahu KK, Agarwal N and Maughan BL: Update on combined immunotherapy for the treatment of advanced renal cell carcinoma. Hum Vaccin Immunother. 19:21935282023. View Article : Google Scholar : PubMed/NCBI

Cafri G, Gartner JJ, Zaks T, Hopson K, Levin N, Paria BC, Parkhurst MR, Yossef R, Lowery FJ, Jafferji MS, et al: mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 130:5976–5988. 2020. View Article : Google Scholar : PubMed/NCBI

Ott PA, Hu-Lieskovan S, Chmielowski B, Govindan R, Naing A, Bhardwaj N, Margolin K, Awad MM, Hellmann MD, Lin JJ, et al: A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. Cell. 183:347–362.e24. 2020. View Article : Google Scholar : PubMed/NCBI

Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, Oliveira G, Giobbie-Hurder A, Felt K, Gjini E, et al: Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 565:234–239. 2019. View Article : Google Scholar :

Platten M, Bunse L, Wick A, Bunse T, Le Cornet L, Harting I, Sahm F, Sanghvi K, Tan CL, Poschke I, et al: A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature. 592:463–468. 2021. View Article : Google Scholar : PubMed/NCBI

Kochenderfer JN, Chien CD, Simpson JL and Gress RE: Maximizing CD8+ T cell responses elicited by peptide vaccines containing CpG oligodeoxynucleotides. Clin Immunol. 124:119–130. 2007. View Article : Google Scholar : PubMed/NCBI

Haining WN, Davies J, Kanzler H, Drury L, Brenn T, Evans J, Angelosanto J, Rivoli S, Russell K, George S, et al: CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans. Clin Cancer Res. 14:5626–5634. 2008. View Article : Google Scholar : PubMed/NCBI

Song YC, Cheng HY, Leng CH, Chiang SK, Lin CW, Chong P, Huang MH and Liu SJ: A novel emulsion-type adjuvant containing CpG oligodeoxynucleotides enhances CD8+ T-cell-mediated anti-tumor immunity. J Control Release. 173:158–165. 2014. View Article : Google Scholar

Baumgaertner P, Costa Nunes C, Cachot A, Maby-El Hajjami H, Cagnon L, Braun M, Derré L, Rivals JP, Rimoldi D, Gnjatic S, et al: Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8⁺ and CD4⁺ T-cell responses with multiple specificities including a novel DR7-restricted epitope. Oncoimmunology. 5:e12162902016. View Article : Google Scholar

Zhu P, Li SY, Ding J, Fei Z, Sun SN, Zheng ZH, Wei D, Jiang J, Miao JL, Li SZ, et al: Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C. J Pharm Anal. 13:616–624. 2023. View Article : Google Scholar : PubMed/NCBI

Soltani M, Savvateeva LV, Ganjalikhani-Hakemi M and Zamyatnin AA: Clinical combinatorial treatments based on cancer vaccines: Combination with checkpoint inhibitors and beyond. Curr Drug Targets. 23:1072–1084. 2022. View Article : Google Scholar : PubMed/NCBI

van der Burg SH, Arens R, Ossendorp F, van Hall T and Melief CJ: Vaccines for established cancer: Overcoming the challenges posed by immune evasion. Nat Rev Cancer. 16:219–233. 2016. View Article : Google Scholar : PubMed/NCBI

Reichmuth AM, Oberli MA, Jaklenec A, Langer R and Blankschtein D: mRNA vaccine delivery using lipid nanoparticles. Ther Deliv. 7:319–334. 2016. View Article : Google Scholar : PubMed/NCBI

Kon E, Ad-El N, Hazan-Halevy I, Stotsky-Oterin L and Peer D: Targeting cancer with mRNA-lipid nanoparticles: Key considerations and future prospects. Nat Rev Clin Oncol. 20:739–754. 2023. View Article : Google Scholar : PubMed/NCBI

Tenchov R, Bird R, Curtze AE and Zhou Q: Lipid nanoparticles-from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano. 15:16982–17015. 2021. View Article : Google Scholar : PubMed/NCBI

Karikó K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S and Weissman D: Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 16:1833–1840. 2008. View Article : Google Scholar : PubMed/NCBI

Ramos da Silva J, Bitencourt Rodrigues K, Formoso Pelegrin G, Silva Sales N, Muramatsu H, de Oliveira Silva M, Porchia BFMM, Moreno ACR, Aps LRMM, Venceslau-Carvalho AA, et al: Single immunizations of self-amplifying or non-replicating mRNA-LNP vaccines control HPV-associated tumors in mice. Sci Transl Med. 15:eabn34642023. View Article : Google Scholar : PubMed/NCBI

Sittplangkoon C, Alameh MG, Weissman D, Lin PJC, Tam YK, Prompetchara E and Palaga T: mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model. Front Immunol. 13:9830002022. View Article : Google Scholar : PubMed/NCBI

Meulewaeter S, Aernout I, Deprez J, Engelen Y, De Velder M, Franceschini L, Breckpot K, Van Calenbergh S, Asselman C, Boucher K, et al: Alpha-galactosylceramide improves the potency of mRNA LNP vaccines against cancer and intracellular bacteria. J Control Release. 370:379–391. 2024. View Article : Google Scholar : PubMed/NCBI

Yang J, Arya S, Lung P, Lin Q, Huang J and Li Q: Hybrid nanovaccine for the co-delivery of the mRNA antigen and adjuvant. Nanoscale. 11:21782–21789. 2019. View Article : Google Scholar : PubMed/NCBI

Carvalho T: Personalized anti-cancer vaccine combining mRNA and immunotherapy tested in melanoma trial. Nat Med. 29:2379–2380. 2023. View Article : Google Scholar : PubMed/NCBI

Podaza E, Carri I, Aris M, von Euw E, Bravo AI, Blanco P, Ortiz Wilczyñski JM, Koile D, Yankilevich P, Nielsen M, et al: Evaluation of T-cell responses against shared melanoma associated antigens and predicted neoantigens in cutaneous melanoma patients treated with the CSF-470 allogeneic cell vaccine plus BCG and GM-CSF. Front Immunol. 11:11472020. View Article : Google Scholar : PubMed/NCBI

Sebastian M, Schröder A, Scheel B, Hong HS, Muth A, von Boehmer L, Zippelius A, Mayer F, Reck M, Atanackovic D, et al: A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer. Cancer Immunol Immunother. 68:799–812. 2019. View Article : Google Scholar : PubMed/NCBI

Zilio S, Bicciato S, Weed D and Serafini P: CCR1 and CCR5 mediate cancer-induced myelopoiesis and differentiation of myeloid cells in the tumor. J Immunother Cancer. 10:e0031312022. View Article : Google Scholar : PubMed/NCBI

Badr G, Al-Sadoon MK, Rabah DM and Sayed D: Snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles induce apoptosis and growth arrest in human prostate cancer cells. Apoptosis. 18:300–314. 2013. View Article : Google Scholar

Badr G, Al-Sadoon MK and Rabah DM: Therapeutic efficacy and molecular mechanisms of snake (Walterinnesia aegyptia) venom-loaded silica nanoparticles in the treatment of breast cancer- and prostate cancer-bearing experimental mouse models. Free Radic Biol Med. 65:175–189. 2013. View Article : Google Scholar : PubMed/NCBI

An S, Tiruthani K, Wang Y, Xu L, Hu M, Li J, Song W, Jiang H, Sun J, Liu R and Huang L: Locally trapping the C-C chemokine receptor type 7 by gene delivery nanoparticle inhibits lymphatic metastasis prior to tumor resection. Small. 15:e18051822019. View Article : Google Scholar : PubMed/NCBI

Liu JQ, Zhang C, Zhang X, Yan J, Zeng C, Talebian F, Lynch K, Zhao W, Hou X, Du S, et al: Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy. J Control Release. 345:306–313. 2022. View Article : Google Scholar : PubMed/NCBI

Li Y, Su Z, Zhao W, Zhang X, Momin N, Zhang C, Wittrup KD, Dong Y, Irvine DJ and Weiss R: Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nat Cancer. 1:882–893. 2020. View Article : Google Scholar

Nguyen KG, Vrabel MR, Mantooth SM, Hopkins JJ, Wagner ES, Gabaldon TA and Zaharoff DA: Localized interleukin-12 for cancer immunotherapy. Front Immunol. 11:5755972020. View Article : Google Scholar : PubMed/NCBI

Xu S, Xu Y, Solek NC, Chen J, Gong F, Varley AJ, Golubovic A, Pan A, Dong S, Zheng G and Li B: Tumor-tailored ionizable lipid nanoparticles facilitate IL-12 circular RNA delivery for enhanced lung cancer immunotherapy. Adv Mater. 36:e24003072024. View Article : Google Scholar : PubMed/NCBI

Fu S, Li G, Zang W, Zhou X, Shi K and Zhai Y: Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy. Acta Pharm Sin B. 12:92–106. 2022. View Article : Google Scholar : PubMed/NCBI

Reda M, Ngamcherdtrakul W, Nelson MA, Siriwon N, Wang R, Zaidan HY, Bejan DS, Reda S, Hoang NH, Crumrine NA, et al: Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment. Nat Commun. 13:42612022. View Article : Google Scholar : PubMed/NCBI

Han X, Wei Q, Lv Y, Weng L, Huang H, Wei Q, Li M, Mao Y, Hua D, Cai X, et al: Ginseng-derived nanoparticles potentiate immune checkpoint antibody efficacy by reprogramming the cold tumor microenvironment. Mol Ther. 30:327–340. 2022. View Article : Google Scholar :

Liu L, Wang Y, Miao L, Liu Q, Musetti S, Li J and Huang L: Combination immunotherapy of MUC1 mRNA nano-vaccine and CTLA-4 blockade effectively inhibits growth of triple negative breast cancer. Mol Ther. 26:45–55. 2018. View Article : Google Scholar :

Ma R, Li Z, Chiocca EA, Caligiuri MA and Yu J: The emerging field of oncolytic virus-based cancer immunotherapy. Trends Cancer. 9:122–139. 2023. View Article : Google Scholar :

Hu H, Zhang S, Cai L, Duan H, Li Y, Yang J, Wang Y and Liu B, Dong S, Fang Z and Liu B: A novel cocktail therapy based on quintuplet combination of oncolytic herpes simplex virus-2 vectors armed with interleukin-12, interleukin-15, GM-CSF, PD1v, and IL-7 × CCL19 results in enhanced antitumor efficacy. Virol J. 19:742022. View Article : Google Scholar

Kim KJ, Moon D, Kong SJ, Lee YS, Yoo Y, Kim S, Kim C, Chon HJ, Kim JH and Choi KJ: Antitumor effects of IL-12 and GM-CSF co-expressed in an engineered oncolytic HSV-1. Gene Ther. 28:186–198. 2021. View Article : Google Scholar

Oh E, Oh JE, Hong J, Chung Y, Lee Y, Park KD, Kim S and Yun CO: Optimized biodegradable polymeric reservoir-mediated local and sustained co-delivery of dendritic cells and oncolytic adenovirus co-expressing IL-12 and GM-CSF for cancer immunotherapy. J Control Release. 259:115–127. 2017. View Article : Google Scholar : PubMed/NCBI

Zhang SN, Choi IK, Huang JH, Yoo JY, Choi KJ and Yun CO: Optimizing DC vaccination by combination with oncolytic adenovirus coexpressing IL-12 and GM-CSF. Mol Ther. 19:1558–1568. 2011. View Article : Google Scholar : PubMed/NCBI

Malhotra J and Kim ES: Oncolytic viruses and cancer immunotherapy. Curr Oncol Rep. 25:19–28. 2023. View Article : Google Scholar