Learning the Roles of the Hepatic Adaptive Immune System in Hepatocellular Carcinoma—Nature's Guide for Successful Cancer Immunotherapy

Mathias Heikenwälder; Eli Pikarsky

doi:10.1055/s-0037-1606255

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2017; 37(03): 210-218
DOI: 10.1055/s-0037-1606255

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Learning the Roles of the Hepatic Adaptive Immune System in Hepatocellular Carcinoma—Nature's Guide for Successful Cancer Immunotherapy

Mathias Heikenwälder

¹Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany

,

Eli Pikarsky

²The Lautenberg Center for Immunology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel

› Author Affiliations

Abstract

The different roles of the adaptive immune system in cancer are beginning to unfold. The dramatic responses to immune check point drugs in some tumors generated an accelerated need for understanding the complex set of interactions between tumor and immune cells. In view of the major pathophysiological role of immune cells in hepatocellular carcinoma, it is not surprising that malignant hepatocytes interact extensively with adaptive immune cells, resulting in both protumor immunopathology and antitumor protective immunity. Identifying potential responders to drugs that target the adaptive immune system, monitoring their immune response to the tumor, and devising the best treatment combinations depends on understanding the complex set of interactions taking place within the tumor and in the adjacent hepatic parenchyma.

Keywords

hepatocellular carcinoma - immunotherapy - immune checkpoint - mouse models - immunosuppression - chronic inflammation

Full Text

References

References
1 Llovet JM, Zucman-Rossi J, Pikarsky E. , et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016; 2: 16018
2 El-Khoueiry AB, Sangro B, Yau T. , 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 2017; 389 (10088): 2492-2502
3 Duffy AG, Ulahannan SV, Makorova-Rusher O. , et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017; 66 (03) 545-551
4 Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 2016; 17 (12) e542-e551
5 Topalian SL, Taube JM, Anders RA, Pardoll DM. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016; 16 (05) 275-287
6 Knolle PA. Staying local-antigen presentation in the liver. Curr Opin Immunol 2016; 40: 36-42
7 Pikarsky E, Heikenwalder M. Focal and local: ectopic lymphoid structures and aggregates of myeloid and other immune cells in liver. Gastroenterology 2016; 151 (05) 780-783
8 Kasper HU, Drebber U, Stippel DL, Dienes HP, Gillessen A. Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma. World J Gastroenterol 2009; 15 (40) 5053-5057
9 Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu; Cancer Genome Atlas Research Network. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 2017; 169 (07) 1327-1341.e23
10 Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology 1998; 27 (02) 407-414
11 Chen KJ, Zhou L, Xie HY, Ahmed TE, Feng XW, Zheng SS. Intratumoral regulatory T cells alone or in combination with cytotoxic T cells predict prognosis of hepatocellular carcinoma after resection. Med Oncol 2012; 29 (03) 1817-1826
12 Chew V, Tow C, Teo M. , et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 2010; 52 (03) 370-379
13 Chew V, Chen J, Lee D. , et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 2012; 61 (03) 427-438
14 Schneider C, Teufel A, Yevsa T. , et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 2012; 61 (12) 1733-1743
15 Sun C, Xu J, Song J. , et al. The predictive value of centre tumour CD8⁺ T cells in patients with hepatocellular carcinoma: comparison with Immunoscore. Oncotarget 2015; 6 (34) 35602-35615
16 Bergis D, Kassis V, Ranglack A. , et al. High serum levels of the interleukin-33 receptor soluble ST2 as a negative prognostic factor in hepatocellular carcinoma. Transl Oncol 2013; 6 (03) 311-318
17 Yamada D, Rizvi S, Razumilava N. , et al. IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism. Hepatology 2015; 61 (05) 1627-1642
18 Li J, Razumilava N, Gores GJ. , et al. Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. J Clin Invest 2014; 124 (07) 3241-3251
19 Villarreal DO, Wise MC, Walters JN. , et al. Alarmin IL-33 acts as an immunoadjuvant to enhance antigen-specific tumor immunity. Cancer Res 2014; 74 (06) 1789-1800
20 Bonilla WV, Fröhlich A, Senn K. , et al. The alarmin interleukin-33 drives protective antiviral CD8⁺ T cell responses. Science 2012; 335 (6071): 984-989
21 Brunner SM, Rubner C, Kesselring R. , et al. Tumor-infiltrating, interleukin-33-producing effector-memory CD8(+) T cells in resected hepatocellular carcinoma prolong patient survival. Hepatology 2015; 61 (06) 1957-1967
22 Sia D, Jiao Y, Martinez-Quetglas I. , et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 2017; ;S0016-5085(17)35741-4 . [Epub ahead of print]
23 Zheng C, Zheng L, Yoo JK. , et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 2017; 169 (07) 1342-1356.e16
24 Garnelo M, Tan A, Her Z. , et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 2017; 66 (02) 342-351
25 Shao Y, Lo CM, Ling CC. , et al. Regulatory B cells accelerate hepatocellular carcinoma progression via CD40/CD154 signaling pathway. Cancer Lett 2014; 355 (02) 264-272
26 Xue H, Lin F, Tan H, Zhu ZQ, Zhang ZY, Zhao L. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4+ T cell activity in HBV-induced hepatocellular carcinoma. PLoS One 2016; 11 (05) e0154815
27 Nishikawa H, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 2014; 27: 1-7
28 Shevach EM. Biological functions of regulatory T cells. Adv Immunol 2011; 112: 137-176
29 Kobayashi N, Hiraoka N, Yamagami W. , et al. FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res 2007; 13 (03) 902-911
30 Wang Y, Liu T, Tang W. , et al. Hepatocellular carcinoma cells induce regulatory T cells and lead to poor prognosis via production of transforming growth factor-β1. Cell Physiol Biochem 2016; 38 (01) 306-318
31 Huang Y, Wang F, Wang Y. , et al. Intrahepatic interleukin-17+ T cells and FoxP3+ regulatory T cells cooperate to promote development and affect the prognosis of hepatocellular carcinoma. J Gastroenterol Hepatol 2014; 29 (04) 851-859
32 Tu JF, Ding YH, Ying XH. , et al. Regulatory T cells, especially ICOS(+) FOXP3(+) regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival. Sci Rep 2016; 6: 35056
33 Fu J, Xu D, Liu Z. , et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007; 132 (07) 2328-2339
34 Gao Q, Qiu SJ, Fan J. , et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25 (18) 2586-2593
35 Zhang AB, Qian YG, Zheng SS. Prognostic significance of regulatory T lymphocytes in patients with hepatocellular carcinoma. J Zhejiang Univ Sci B 2016; 17 (12) 984-991
36 Zhao HQ, Li WM, Lu ZQ, Yao YM. Roles of Tregs in development of hepatocellular carcinoma: a meta-analysis. World J Gastroenterol 2014; 20 (24) 7971-7978
37 Hefetz-Sela S, Stein I, Klieger Y. , et al. Acquisition of an immunosuppressive protumorigenic macrophage phenotype depending on c-Jun phosphorylation. Proc Natl Acad Sci U S A 2014; 111 (49) 17582-17587
38 Taketomi A, Shimada M, Shirabe K, Kajiyama K, Gion T, Sugimachi K. Natural killer cell activity in patients with hepatocellular carcinoma: a new prognostic indicator after hepatectomy. Cancer 1998; 83 (01) 58-63
39 Liu HZ, Deng W, Li JL. , et al. Peripheral blood lymphocyte subset levels differ in patients with hepatocellular carcinoma. Oncotarget 2016; 7 (47) 77558-77564
40 Cariani E, Pilli M, Barili V. , et al. Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments. OncoImmunology 2016; 5 (08) e1154249
41 Tian Z, Chen Y, Gao B. Natural killer cells in liver disease. Hepatology 2013; 57 (04) 1654-1662
42 Cariani E, Missale G. KIR/HLA immunogenetic background influences the evolution of hepatocellular carcinoma. OncoImmunology 2013; 2 (12) e26622
43 Kumar V, Kato N, Urabe Y. , et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011; 43 (05) 455-458
44 Goto K, Annan DA, Morita T. , et al. Novel chemoimmunotherapeutic strategy for hepatocellular carcinoma based on a genome-wide association study. Sci Rep 2016; 6: 38407
45 Tanimine N, Tanaka Y, Kobayashi T. , et al. Quantitative effect of natural killer-cell licensing on hepatocellular carcinoma recurrence after curative hepatectomy. Cancer Immunol Res 2014; 2 (12) 1142-1147
46 Sun C, Xu J, Huang Q. , et al. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. OncoImmunology 2016; 6 (01) e1264562
47 Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 2015; 161 (02) 205-214
48 Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 2015; 27 (04) 450-461
49 Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 2013; 14 (12) 1212-1218
50 Sangro B, Gomez-Martin C, de la Mata M. , et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013; 59 (01) 81-88
51 Mizukoshi E, Yamashita T, Arai K. , et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology 2013; 57 (04) 1448-1457
52 Hiroishi K, Eguchi J, Baba T. , et al. Strong CD8(+) T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J Gastroenterol 2010; 45 (04) 451-458
53 Nobuoka D, Motomura Y, Shirakawa H. , et al. Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes. Int J Oncol 2012; 40 (01) 63-70
54 Hansler J, Wissniowski TT, Schuppan D. , et al. Activation and dramatically increased cytolytic activity of tumor specific T lymphocytes after radio-frequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases. World J Gastroenterol 2006; 12 (23) 3716-3721
55 Le DT, Uram JN, Wang H. , et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26) 2509-2520
56 Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature 2011; 480 (7378): 480-489
57 Topalian SL, Hodi FS, Brahmer JR. , et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366 (26) 2443-2454
58 Boutros C, Tarhini A, Routier E. , et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol 2016; 13 (08) 473-486
59 Reck M, Rodríguez-Abreu D, Robinson AG. , et al; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375 (19) 1823-1833
60 Neuman T, London M, Kania-Almog J. , et al. A harmonization study for the use of 22C3 PD-L1 immunohistochemical staining on Ventana's platform. J Thorac Oncol 2016; 11 (11) 1863-1868
61 Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res 2017
62 Finkin S, Yuan D, Stein I. , et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol 2015; 16 (12) 1235-1244
63 Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol 2012; 12 (03) 201-213
64 Haybaeck J, Zeller N, Wolf MJ. , et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 2009; 16 (04) 295-308
65 Endig J, Buitrago-Molina LE, Marhenke S. , et al. Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell 2016; 30 (02) 308-323
66 Wolf MJ, Adili A, Piotrowitz K. , et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell 2014; 26 (04) 549-564
67 Ehlken H, Krishna-Subramanian S, Ochoa-Callejero L. , et al. Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout. Cell Death Differ 2014; 21 (11) 1721-1732
68 Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. Immune pathogenesis of hepatocellular carcinoma. J Exp Med 1998; 188 (02) 341-350
69 Willimsky G, Blankenstein T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 2005; 437 (7055): 141-146
70 Ma C, Kesarwala AH, Eggert T. , et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016; 531 (7593): 253-257
71 Kang TW, Yevsa T, Woller N. , et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 2011; 479 (7374): 547-551
72 Gomes AL, Teijeiro A, Burén S. , et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell 2016; 30 (01) 161-175
73 Qi H, Kastenmüller W, Germain RN. Spatiotemporal basis of innate and adaptive immunity in secondary lymphoid tissue. Annu Rev Cell Dev Biol 2014; 30: 141-167
74 Huang LR, Wohlleber D, Reisinger F. , et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol 2013; 14 (06) 574-583
75 Leslie M. Immunity goes local. Science 2016; 352 (6281): 21-23
76 Sautès-Fridman C, Lawand M, Giraldo NA. , et al. Tertiary lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front Immunol 2016; 7: 407
77 Coppola D, Nebozhyn M, Khalil F. , et al. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am J Pathol 2011; 179 (01) 37-45
78 Messina JL, Fenstermacher DA, Eschrich S. , et al. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy?. Sci Rep 2012; 2: 765
79 Ramzan M, Sturm N, Decaens T. , et al. Liver-infiltrating CD8(+) lymphocytes as prognostic factor for tumour recurrence in hepatitis C virus-related hepatocellular carcinoma. Liver Int 2016; 36 (03) 434-444