Classification of tumor microenvironment immune types based on immune response-associated gene expression

Kondou,Ryota; Iizuka,Akira; Nonomura,Chizu; Miyata,Haruo; Ashizawa,Tadashi; Nagashima,Takeshi; Ohshima,Keiichi; Urakami,Kenichi; Kusuhara,Masatoshi; Yamaguchi,Ken; Akiyama,Yasuto

doi:10.3892/ijo.2018.4617

Classification of tumor microenvironment immune types based on immune response-associated gene expression

Authors:
- Ryota Kondou
- Akira Iizuka
- Chizu Nonomura
- Haruo Miyata
- Tadashi Ashizawa
- Takeshi Nagashima
- Keiichi Ohshima
- Kenichi Urakami
- Masatoshi Kusuhara
- Ken Yamaguchi
- Yasuto Akiyama
View Affiliations

Affiliations: Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka 411-8777, Japan, SRL Inc., Tokyo 191-0002, Japan, Medical Genetics Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Shizuoka 411-8777, Japan, Cancer Diagnostic Research Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Shizuoka 411-8777, Japan, Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka Cancer Center Hospital, Shizuoka 411-8777, Japan, Office of the President, Shizuoka Cancer Center Hospital, Shizuoka 411-8777, Japan
Published online on: November 2, 2018 https://doi.org/10.3892/ijo.2018.4617
Pages: 219-228

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In 2014, the Shizuoka Cancer Center launched project High‑tech Omics‑based Patient Evaluation (HOPE), which features whole exome sequencing (WES) and gene expression profiling (GEP) of fresh surgical specimens from cancer patients. With the development of clinical trials of programmed death‑1 (PD‑1)/PD‑ligand 1 (PD‑L1) blockade, PD‑L1 expression and a high tumor mutation burden become possible biomarkers that could be used to predict immune responses. In this study, based on WES and GEP data from 1,734 tumors from the HOPE project, we established a tumor microenvironment (TME) immune‑type classification consisting of 4 types to evaluate the immunological status of cancer patients and analyze immunological pathways specific for immune types. Project HOPE was conducted in accordance with the Ethical Guidelines for Human Genome and Genetic Analysis Research with the approval of the Institutional Review Board. Based on the expression level of the PD‑L1 and CD8B genes, the immunological status was divided into 4 types as follows: A, PD‑L1+CD8B+; B, PD‑L1+CD8B‑; C, PD‑L1‑CD8B‑; and D, PD‑L1‑CD8B+. Type A, with PD‑L1+ and CD8B+, exhibited an upregulation of cytotoxic T lymphocyte (CTL) killing‑associated genes, T‑cell activation genes, antigen‑presentation and dendritic cell (DC) maturation genes, and T‑cell‑attracting chemokine genes, which promoted Th1 antitumor responses. By contrast, type C, with PD‑L1‑ and CD8B‑, exhibited a low expression of T‑cell‑activating genes and an upregulation of cancer driver gene signaling, which suggested an immune‑suppressive status. With regard to hypermutator tumors, PD‑L1+ hypermutator cases exhibited a specific upregulation of the IL6 gene compared with the PD‑L1‑ cases. On the whole, our data indicate that the classification of the TME immune types may prove to be a useful tool for evaluating the immunological status and predicting antitumor responses and prognosis.

View Figures

View References

1	Weber JS, O'Day S, Urba W, Powderly J, Nichol G, Yellin M, Snively J and Hersh E: Phase I/II study of ipilimumab for patients with metastatic melanoma. J Clin Oncol. 26:5950–5956. 2008. View Article : Google Scholar : PubMed/NCBI
2	Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 363:711–723. 2010. View Article : Google Scholar : PubMed/NCBI
3	Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 366:2443–2454. 2012. View Article : Google Scholar : PubMed/NCBI
4	Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 366:2455–2465. 2012. View Article : Google Scholar : PubMed/NCBI
5	Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, et al: Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 369:122–133. 2013. View Article : Google Scholar : PubMed/NCBI
6	Couzin-Frankel J: Breakthrough of the year 2013. Cancer immunotherapy. Science. 342:1432–1433. 2013. View Article : Google Scholar : PubMed/NCBI
7	Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, Walsh LA, Postow MA, Wong P, Ho TS, et al: Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 371:2189–2199. 2014. View Article : Google Scholar : PubMed/NCBI
8	Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, et al KEYNOTE-001 Investigators: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 372:2018–2028. 2015. View Article : Google Scholar : PubMed/NCBI
9	Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al KEYNOTE-024 Investigators: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 375:1823–1833. 2016. View Article : Google Scholar : PubMed/NCBI
10	Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, et al: Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 357:409–413. 2017. View Article : Google Scholar : PubMed/NCBI
11	Dahlin AM, Henriksson ML, Van Guelpen B, Stenling R, Öberg A, Rutegård J and Palmqvist R: Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor. Mod Pathol. 24:671–682. 2011. View Article : Google Scholar : PubMed/NCBI
12	Llosa NJ, Cruise M, Tam A, Wicks EC, Hechenbleikner EM, Taube JM, Blosser RL, Fan H, Wang H, Luber BS, et al: The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5:43–51. 2015. View Article : Google Scholar :
13	Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, Herbst RS and Rimm DL: Objective measurement and clinical significance of TILs in non-small cell lung cancer. J Natl Cancer Inst. 107:dju4352015. View Article : Google Scholar : PubMed/NCBI
14	Rooney MS, Shukla SA, Wu CJ, Getz G and Hacohen N: Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 160:48–61. 2015. View Article : Google Scholar : PubMed/NCBI
15	Ock CY, Keam B, Kim S, Lee JS, Kim M, Kim TM, Jeon YK, Kim DW, Chung DH and Heo DS: Pan-cancer immunogenic perspective on the tumor microenvironment based on PD-L1 and CD8 T-cell infiltration. Clin Cancer Res. 22:2261–2270. 2016. View Article : Google Scholar : PubMed/NCBI
16	Yamaguchi K, Urakami K, Nagashima T, Shimoda Y, Ohnami S, Ohnami S, Ohshima K, Mochizuki T, Hatakeyama K, Serizawa M, et al: Prevalence of low-penetrant germline TP53 D49H mutation in Japanese cancer patients. Biomed Res. 37:259–264. 2016. View Article : Google Scholar : PubMed/NCBI
17	Ohshima K, Hatakeyama K, Nagashima T, Watanabe Y, Kanto K, Doi Y, Ide T, Shimoda Y, Tanabe T, Ohnami S, et al: Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors. Sci Rep. 7:6412017. View Article : Google Scholar : PubMed/NCBI
18	Akiyama Y, Kondou R, Iizuka A, Ohshima K, Urakami K, Nagashima T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, et al: Immune response-associated gene analysis of 1,000 cancer patients using whole-exome sequencing and gene expression profiling-Project HOPE. Biomed Res. 37:233–242. 2016. View Article : Google Scholar : PubMed/NCBI
19	Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, et al: Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet. 29:365–371. 2001. View Article : Google Scholar : PubMed/NCBI
20	Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr and Kinzler KW: Cancer genome landscapes. Science. 339:1546–1558. 2013. View Article : Google Scholar : PubMed/NCBI
21	Papalexi E and Satija R: Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol. 18:35–45. 2018. View Article : Google Scholar
22	Teng MW, Ngiow SF, Ribas A and Smyth MJ: Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res. 75:2139–2145. 2015. View Article : Google Scholar : PubMed/NCBI
23	Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pagès F, et al: Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 71:1263–1271. 2011. View Article : Google Scholar : PubMed/NCBI
24	Ascierto RA, Capone M, Urba WJ, Bifuco CB, Botti G, Lugli A, Marincola FM, Ciliberto G, Galon J and Fox BA: The additional facet of immunoscore: immunoprofiling as a possible predictive tool for cancer treatment. J Transl Med. 11:542913. View Article : Google Scholar
25	Lee HJ, Lee JJ, Song IH, Park IA, Kang J, Yu JH, Ahn JH and Gong G: Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: Relationship to tumor-infiltrating lymphocytes. Breast Cancer Res Treat. 151:619–627. 2015. View Article : Google Scholar : PubMed/NCBI
26	Gnjatic S, Bronte V, Brunet LR, Butler MO, Disis ML, Galon J, Hakansson LG, Hanks BA, Karanikas V, Khleif SN, et al: Identifying baseline immune-related biomarkers to predict clinical outcome of immunotherapy. J Immunother Cancer. 5:442017. View Article : Google Scholar : PubMed/NCBI
27	Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, et al: IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 127:2930–2940. 2017. View Article : Google Scholar : PubMed/NCBI
28	Stroncek DF, Butterfield LH, Cannarile MA, Dhodapkar MV, Greten TF, Grivel JC, Kaufman DR, Kong HH, Korangy F, Lee PP, et al: Systematic evaluation of immune regulation and modulation. J Immunother Cancer. 5:212017. View Article : Google Scholar : PubMed/NCBI
29	Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X, Ennis RC, Fabrizio D, Chalmers ZR, Greenbowe J, et al: Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunol Res. 4:959–967. 2016. View Article : Google Scholar : PubMed/NCBI
30	Dudley JC, Lin MT, Le DT and Eshleman JR: Microsatellite instability as a biomarker for PD-1 blockade. Clin Cancer Res. 22:813–820. 2016. View Article : Google Scholar : PubMed/NCBI
31	Gong J, Wang C, Lee PP, Chu P and Fakih M: Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation. J Natl Compr Canc Netw. 15:142–147. 2017. View Article : Google Scholar : PubMed/NCBI
32	Prat A, Navarro A, Paré L, Reguart N, Galván P, Pascual T, Martínez A, Nuciforo P, Comerma L, Alos L, et al: Immune-related gene expression profiling after PD-1 blockade in non-small cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma. Cancer Res. 77:3540–3550. 2017. View Article : Google Scholar : PubMed/NCBI