Tumor‑infiltrating CD8<sup>+</sup> T cells as a biomarker for chemotherapy efficacy in unresectable hepatocellular carcinoma

Kuwano,Akifumi; Yada,Masayoshi; Miyazaki,Yoshiko; Tanaka,Kosuke; Kurosaka,Kazuki; Ohishi,Yoshihiro; Masumoto,Akihide; Motomura,Kenta

doi:10.3892/ol.2023.13845

June-2023 Volume 25 Issue 6

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June-2023 Volume 25 Issue 6

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Article Open Access

Tumor‑infiltrating CD8⁺ T cells as a biomarker for chemotherapy efficacy in unresectable hepatocellular carcinoma

Authors:
- Akifumi Kuwano
- Masayoshi Yada
- Yoshiko Miyazaki
- Kosuke Tanaka
- Kazuki Kurosaka
- Yoshihiro Ohishi
- Akihide Masumoto
- Kenta Motomura
View Affiliations / Copyright

Affiliations: Department of Hepatology, Aso Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan, Department of Diagnostic Pathology, Aso Iizuka Hospital, Iizuka, Fukuoka 820‑8505, Japan

Copyright: © Kuwano et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 259
|
Published online on: April 28, 2023

https://doi.org/10.3892/ol.2023.13845
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Abstract

Atezolizumab plus bevacizumab and lenvatinib are approved frontline therapies for advanced hepatocellular carcinoma (HCC). Patients with advanced HCC continue to have a poor prognosis despite these therapeutic choices. Previous studies have reported CD8⁺ tumor‑infiltrating lymphocytes (TILs) as a biomarker to predict responsiveness to systemic chemotherapy. The present study investigated whether evaluating CD8⁺ TILs by immunohistochemistry staining of liver tumor biopsy tissues could help predict the response of patients with HCC to atezolizumab plus bevacizumab and lenvatinib. In total, 39 patients with HCC who underwent liver tumor biopsy were classified into high and low CD8⁺ TILs groups and were then divided by therapy type. The clinical responses to treatment in both groups were evaluated for each therapy. There were 12 patients with high‑level CD8⁺ TILs and 12 patients with low‑level CD8⁺ TILs among those who received atezolizumab plus bevacizumab. An improved response rate was observed in the high‑level group compared with the low‑level group. The high‑level CD8⁺ TILs group had a significantly longer median progression‑free survival compared with the low‑level group. Among the patients with HCC who received lenvatinib, five had high‑level CD8⁺ TILs and 10 had low‑level CD8⁺ TILs. There were no differences in response rate or progression‑free survival between these groups. Although the present study included only a limited number of patients, the findings suggested that CD8⁺ TILs could be a biomarker for predicting response to systemic chemotherapy in HCC.

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1	Caldwell S and Park SH: The epidemiology of hepatocellular cancer: From the perspectives of public health problem to tumor biology. J Gastroenterol. 44:96–101. 2009. View Article : Google Scholar : PubMed/NCBI
2	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
3	Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, Kudo M, Breder V, Merle P, Kaseb AO, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 382:1894–1905. 2020. View Article : Google Scholar : PubMed/NCBI
4	Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, et al: Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial. Lancet. 391:1163–1173. 2018. View Article : Google Scholar : PubMed/NCBI
5	El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, Choo SP, Trojan J, Welling TH Rd, et al: Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): An open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 389:2492–2502. 2017. View Article : Google Scholar : PubMed/NCBI
6	Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, Verslype C, Zagonel V, Fartoux L, Vogel A, et al: Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): A non-randomised, open-label phase 2 trial. Lancet Oncol. 19:940–952. 2018. View Article : Google Scholar : PubMed/NCBI
7	Eso Y and Marusawa H: Novel approaches for molecular targeted therapy against hepatocellular carcinoma. Hepatol Res. 48:597–607. 2018. View Article : Google Scholar : PubMed/NCBI
8	Tohyama O, Matsui J, Kodama K, Hata-Sugi N, Kimura T, Okamoto K, Minoshima Y, Iwata M and Funahashi Y: Antitumor activity of lenvatinib (e7080): An angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res. 2014:6387472014. View Article : Google Scholar : PubMed/NCBI
9	Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, Nakamura K, Tohyama O, Semba T, Yamaguchi A, Hoshi SS, et al: Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell. 6:182014. View Article : Google Scholar : PubMed/NCBI
10	Hurkmans DP, Kuipers ME, Smit J, van Marion R, Mathijssen RHJ, Postmus PE, Hiemstra PS, Aerts JGJV, von der Thüsen JH and van der Burg SH: Tumor mutational load, CD8+ T cells, expression of PD-L1 and HLA class I to guide immunotherapy decisions in NSCLC patients. Cancer Immunol Immunother. 69:771–777. 2020. View Article : Google Scholar : PubMed/NCBI
11	Li F, Li C, Cai X, Xie Z, Zhou L, Cheng B, Zhong R, Xiong S, Li J, Chen Z, et al: The association between CD8⁺ tumor-infiltrating lymphocytes and the clinical outcome of cancer immunotherapy: A systematic review and meta-analysis. EClinicalMedicine. 41:1011342021. View Article : Google Scholar : PubMed/NCBI
12	Rimini M, Rimassa L, Ueshima K, Burgio V, Shigeo S, Tada T, Suda G, Yoo C, Cheon J, Pinato DJ, et al: Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: An international propensity score matching analysis. ESMO Open. 7:1005912022. View Article : Google Scholar : PubMed/NCBI
13	Zhu AX, Abbas AR, de Galarreta MR, Guan Y, Lu S, Koeppen H, Zhang W, Hsu CH, He AR, Ryoo BY, et al: Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat Med. 28:1599–1611. 2022. View Article : Google Scholar : PubMed/NCBI
14	Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O'Beirne J, Fox R, Skowronska A, Palmer D, et al: Assessment of liver function in patients with hepatocellular carcinoma: A new evidence-based approach-the ALBI grade. J Clin Oncol. 33:550–558. 2015. View Article : Google Scholar : PubMed/NCBI
15	Lencioni R and Llovet JM: Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 30:52–60. 2010. View Article : Google Scholar : PubMed/NCBI
16	Montironi C, Castet F, Haber PK, Pinyol R, Torres-Martin M, Torrens L, Mesropian A, Wang H, Puigvehi M, Maeda M, et al: Inflamed and non-inflamed classes of HCC: A revised immunogenomic classification. Gut. 72:129–140. 2022. View Article : Google Scholar : PubMed/NCBI
17	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
18	Pinyol R, Sia D and Llovet JM: Immune Exclusion-Wnt/CTNNB1 class predicts resistance to immunotherapies in HCC. Clin Cancer Res. 25:2021–2023. 2019. View Article : Google Scholar : PubMed/NCBI
19	Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, Shia J, Hechtman JF, Kundra R, El Dika I, et al: Prospective genotyping of hepatocellular carcinoma: Clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 25:2116–2126. 2019. View Article : Google Scholar : PubMed/NCBI
20	Chen L, Zhou Q, Liu J and Zhang W: CTNNB1 alternation is a potential biomarker for immunotherapy prognosis in patients with hepatocellular carcinoma. Front Immunol. 12:7595652021. View Article : Google Scholar : PubMed/NCBI
21	Bai R, Lv Z, Xu D and Cui J: Predictive biomarkers for cancer immunotherapy with immune checkpoint inhibitors. Biomarker Res. 8:342020. View Article : Google Scholar : PubMed/NCBI
22	Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, et al: Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 378:2093–2104. 2018. View Article : Google Scholar : PubMed/NCBI
23	Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial. Lancet. 387:1909–1920. 2016. View Article : Google Scholar : PubMed/NCBI
24	Gibney GT, Weiner LM and Atkins MB: Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 17:e542–e551. 2016. View Article : Google Scholar : PubMed/NCBI
25	Cristescu R, Mogg R, Ayers M, Albright A, Murphy E, Yearley J, Sher X, Liu XQ, Lu H, Nebozhyn M, et al: Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 362:eaar35932018. View Article : Google Scholar : PubMed/NCBI
26	Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, Luciani A, Zafrani ES, Laurent A, Azoulay D, et al: Programmed death ligand 1 expression in hepatocellular carcinoma: Relationship with clinical and pathological features. Hepatology. 64:2038–2046. 2016. View Article : Google Scholar : PubMed/NCBI
27	Dhanasekaran R, Nault JC, Roberts LR and Zucman-Rossi J: Genomic medicine and implications for hepatocellular carcinoma prevention and therapy. Gastroenterology. 156:492–509. 2019. View Article : Google Scholar : PubMed/NCBI
28	Tsuta K, Ishii G, Kim E, Shiono S, Nishiwaki Y, Endoh Y, Kodama T and Nagai K and Nagai K: Primary lung adenocarcinoma with massive lymphocyte infiltration. Am J Clin Pathol. 123:547–552. 2005. View Article : Google Scholar : PubMed/NCBI
29	Canna K, McArdle PA, McMillan DC, McNicol AM, Smith GW, McKee RF and McArdle CS: The relationship between tumour T-lymphocyte infiltration, the systemic inflammatory response and survival in patients undergoing curative resection for colorectal cancer. Br J Cancer. 92:651–654. 2005. View Article : Google Scholar : PubMed/NCBI
30	Schondorf T, Engel H, Lindemann C, Kolhagen H, von Rucker AA and Mallmann P: Cellular characteristics of peripheral blood lymphocytes and tumour-infiltrating lymphocytes in patients with gynaecological tumours. Cancer Immunol Immunother. 44:88–96. 1997. View Article : Google Scholar : PubMed/NCBI
31	Ben-Hur H, Cohen O, Schneider D, Gurevich P, Halperin R, Bala U, Mozes M and Zusman I: The role of lymphocytes and macrophages in human breast tumorigenesis: An immunohistochemical and morphometric study. Anticancer Res. 22:1231–1238. 2002.PubMed/NCBI
32	Leong PP, Mohammad R, Ibrahim N, Ithnin H, Abdullah M, Davis WC and Seow HF: Phenotyping of lymphocytes expressing regulatory and effector markers in infiltrating ductal carcinoma of the breast. Immunol Lett. 102:229–236. 2006. View Article : Google Scholar : PubMed/NCBI
33	Schillaci R, Salatino M, Cassataro J, Proietti CJ, Giambartolomei GH, Rivas MA, Carnevale RP, Charreau EH and Elizalde PV: Immunization with murine breast cancer cells treated with antisense oligodeoxynucleotides to type I insulin-like growth factor receptor induced an antitumoral effect mediated by a CD8⁺ response involving Fas/Fas ligand cytotoxic pathway. J Immunol. 176:3426–3437. 2006. View Article : Google Scholar : PubMed/NCBI
34	Dobrzanski MJ, Reome JB, Hylind JC and Rewers-Felkins KA: CD8-mediated type 1 antitumor responses selectively modulate endogenous differentiated and nondifferentiated T cell localization, activation, and function in progressive breast cancer. J Immunol. 177:8191–8201. 2006. View Article : Google Scholar : PubMed/NCBI
35	Huh JW, Lee JH and Kim HR: Prognostic significance of tumor-infiltrating lymphocytes for patients with colorectal cancer. Arch Surg. 147:366–372. 2012. View Article : Google Scholar : PubMed/NCBI
36	Tokito T, Azuma K, Kawahara A, Ishii H, Yamada K, Matsuo N, Kinoshita T, Mizukami N, Ono H, Kage M, et al: Predictive relevance of PD-L1 expression combined with CD8⁺ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. Eur J Cancer. 55:7–14. 2016. View Article : Google Scholar : PubMed/NCBI
37	Liu S, Lachapelle J, Leung S, Gao D, Foulkes WD and Nielsen TO: CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Br Cancer Res. 14:R482012. View Article : Google Scholar : PubMed/NCBI
38	Hsu CL, Ou DL, Bai LY, Chen CW, Lin L, Huang SF, Cheng AL, Jeng YM and Hsu C: Exploring markers of exhausted CD8 T cells to predict response to immune checkpoint inhibitor therapy for hepatocellular carcinoma. Liver Cancer. 10:346–359. 2021. View Article : Google Scholar : PubMed/NCBI
39	Sohn BH, Park IY, Shin JH, Yim SY and Lee JS: Glutamine synthetase mediates sorafenib sensitivity in β-catenin-active hepatocellular carcinoma cells. Exp Mol Med. 50:e4212018. View Article : Google Scholar : PubMed/NCBI

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