. 2021 Aug; 126(1):10-23.
doi: 10.1038/s41416-021-01453-3.

Immune suppressive checkpoint interactions in the tumour microenvironment of primary liver cancers

Guoying Zhou 1 Patrick P C Boor 2 Marco J Bruno 2 Dave Sprengers 2 Jaap Kwekkeboom 2 
  • PMID: 34400801
  •     177 References
  •     1 citations


Liver cancer is one of the most prevalent cancers, and the third most common cause of cancer-related mortality worldwide. The therapeutic options for the main types of primary liver cancer-hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA)-are very limited. HCC and CCA are immunogenic cancers, but effective immune-mediated tumour control is prevented by their immunosuppressive tumour microenvironment. Despite the critical involvement of key co-inhibitory immune checkpoint interactions in immunosuppression in liver cancer, only a minority of patients with HCC respond to monotherapy using approved checkpoint inhibitor antibodies. To develop effective (combinatorial) therapeutic immune checkpoint strategies for liver cancer, in-depth knowledge of the different mechanisms that contribute to intratumoral immunosuppression is needed. Here, we review the co-inhibitory pathways that are known to suppress intratumoral T cells in HCC and CCA. We provide a detailed description of insights from preclinical studies in cellular crosstalk within the tumour microenvironment that results in interactions between co-inhibitory receptors on different T-cell subsets and their ligands on other cell types, including tumour cells. We suggest alternative immune checkpoints as promising targets, and draw attention to the possibility of combined targeting of co-inhibitory and co-stimulatory pathways to abrogate immunosuppression.

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N Engl J Med, 2020 May 14; 382(20). PMID: 32402160
LAG-3 in Cancer Immunotherapy.
Monica V Goldberg, Charles G Drake.
Curr Top Microbiol Immunol, 2010 Nov 19; 344. PMID: 21086108    Free PMC article.
Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma.
Eishiro Mizukoshi, Yasunari Nakamoto, +7 authors, Shuichi Kaneko.
Hepatology, 2011 Apr 12; 53(4). PMID: 21480325
Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer.
Alexander Pedroza-Gonzalez, Cornelis Verhoef, +5 authors, Dave Sprengers.
Hepatology, 2012 Aug 23; 57(1). PMID: 22911397
Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota.
Marine Fidelle, Satoru Yonekura, +4 authors, Laurence Zitvogel.
Front Immunol, 2021 Jan 01; 11. PMID: 33381121    Free PMC article.
Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma.
Richard S Finn, Masafumi Ikeda, +17 authors, Josep M Llovet.
J Clin Oncol, 2020 Jul 28; 38(26). PMID: 32716739    Free PMC article.
Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.
Andrea Schietinger, Mary Philip, +10 authors, Philip D Greenberg.
Immunity, 2016 Aug 16; 45(2). PMID: 27521269    Free PMC article.
Highly Cited.
Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.
Thomas Yau, Chiun Hsu, +14 authors, Masatoshi Kudo.
J Hepatol, 2019 Jun 10; 71(3). PMID: 31176752
Highly Cited.
FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells.
Lucia Campos Carrascosa, Adriaan A van Beek, +19 authors, Jaap Kwekkeboom.
J Immunother Cancer, 2020 Sep 10; 8(2). PMID: 32900860    Free PMC article.
Immunotherapy in Solid Tumors and Gut Microbiota: The Correlation-A Special Reference to Colorectal Cancer.
Asimina Koulouridi, Ippokratis Messaritakis, +2 authors, John Souglakos.
Cancers (Basel), 2020 Dec 31; 13(1). PMID: 33375686    Free PMC article.
Aberrant expression of B7-H4 correlates with poor prognosis and suppresses tumor-infiltration of CD8+ T lymphocytes in human cholangiocarcinoma.
Xin Zhao, Fei Guo, +5 authors, Shuguang Wang.
Oncol Rep, 2016 May 14; 36(1). PMID: 27177355
Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.
Antoni Ribas, Omid Hamid, +25 authors, Caroline Robert.
JAMA, 2016 Apr 20; 315(15). PMID: 27092830
Highly Cited.
TOX promotes the exhaustion of antitumor CD8+ T cells by preventing PD1 degradation in hepatocellular carcinoma.
Xiaochen Wang, Qifeng He, +4 authors, Beicheng Sun.
J Hepatol, 2019 Jun 08; 71(4). PMID: 31173813
Highly Cited.
Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas.
Guoying Zhou, Dave Sprengers, +13 authors, Jaap Kwekkeboom.
Gastroenterology, 2017 Jun 27; 153(4). PMID: 28648905
Highly Cited.
Expression of class I MHC molecule, HSP70 and TAP in human hepatocellular carcinoma.
Xiao-Ling Deng, Wei Chen, Mei-Ying Cai, Da-Peng Wei.
World J Gastroenterol, 2003 Aug 15; 9(8). PMID: 12918137    Free PMC article.
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.
Jedd D Wolchok, Vanna Chiarion-Sileni, +30 authors, James Larkin.
N Engl J Med, 2017 Sep 12; 377(14). PMID: 28889792    Free PMC article.
Highly Cited.
B7-H3 promotes aggression and invasion of hepatocellular carcinoma by targeting epithelial-to-mesenchymal transition via JAK2/STAT3/Slug signaling pathway.
Fu-Biao Kang, Ling Wang, +4 authors, Dian-Xing Sun.
Cancer Cell Int, 2015 Apr 25; 15. PMID: 25908926    Free PMC article.
Immune checkpoint inhibitors in advanced renal cell carcinoma: experience to date and future directions.
M B Atkins, J I Clark, D I Quinn.
Ann Oncol, 2017 Apr 07; 28(7). PMID: 28383639
Characterization of the Immune Microenvironment in Hepatocellular Carcinoma.
Mark Yarchoan, Dongmei Xing, +9 authors, Robert A Anders.
Clin Cancer Res, 2017 Sep 21; 23(23). PMID: 28928158    Free PMC article.
Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Emanuela Romano, Monika Kusio-Kobialka, +7 authors, Daniel E Speiser.
Proc Natl Acad Sci U S A, 2015 Apr 29; 112(19). PMID: 25918390    Free PMC article.
Highly Cited.
Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response.
Xiaoqiang Qi, Ming Yang, +8 authors, Guangfu Li.
J Immunother Cancer, 2020 Oct 30; 8(2). PMID: 33115942    Free PMC article.
Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions.
Yan Wu, Dong-Ming Kuang, +5 authors, Limin Zheng.
Hepatology, 2012 Dec 12; 57(3). PMID: 23225218
Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial.
Thomas Yau, Yoon-Koo Kang, +18 authors, Chiun Hsu.
JAMA Oncol, 2020 Oct 02; 6(11). PMID: 33001135    Free PMC article.
Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma.
Chun Jye Lim, Yun Hua Lee, +15 authors, Valerie Chew.
Gut, 2018 Jul 05; 68(5). PMID: 29970455
Highly Cited.
Mechanisms regulating T-cell infiltration and activity in solid tumors.
E Lanitis, D Dangaj, M Irving, G Coukos.
Ann Oncol, 2017 Oct 19; 28(suppl_12). PMID: 29045511
Highly Cited.
CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice.
Yunching Chen, Rakesh R Ramjiawan, +13 authors, Dan G Duda.
Hepatology, 2014 Dec 23; 61(5). PMID: 25529917    Free PMC article.
Highly Cited.
Identification of CD112R as a novel checkpoint for human T cells.
Yuwen Zhu, Alessandro Paniccia, +6 authors, Barish H Edil.
J Exp Med, 2016 Jan 13; 213(2). PMID: 26755705    Free PMC article.
Pathogenesis, diagnosis, and management of cholangiocarcinoma.
Sumera Rizvi, Gregory J Gores.
Gastroenterology, 2013 Oct 22; 145(6). PMID: 24140396    Free PMC article.
Highly Cited. Review.
Intratumoral heterogeneity and clonal evolution in liver cancer.
Bojan Losic, Amanda J Craig, +25 authors, Augusto Villanueva.
Nat Commun, 2020 Jan 17; 11(1). PMID: 31941899    Free PMC article.
Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy.
Jingying Zhou, Man Liu, +17 authors, Alfred Sze-Lok Cheng.
Gut, 2017 Sep 25; 67(5). PMID: 28939663    Free PMC article.
Neoantigens in cancer immunotherapy.
Ton N Schumacher, Robert D Schreiber.
Science, 2015 Apr 04; 348(6230). PMID: 25838375
Highly Cited. Review.
Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.
Ana C Anderson, Nicole Joller, Vijay K Kuchroo.
Immunity, 2016 May 19; 44(5). PMID: 27192565    Free PMC article.
Highly Cited. Review.
Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape.
Seng-Ryong Woo, Meghan E Turnis, +18 authors, Dario A A Vignali.
Cancer Res, 2011 Dec 22; 72(4). PMID: 22186141    Free PMC article.
Highly Cited.
Lenvatinib: A Review in Hepatocellular Carcinoma.
Zaina T Al-Salama, Yahiya Y Syed, Lesley J Scott.
Drugs, 2019 Apr 18; 79(6). PMID: 30993651
Coinhibitory receptor PD-1H preferentially suppresses CD4⁺ T cell-mediated immunity.
Dallas B Flies, Xue Han, +4 authors, Lieping Chen.
J Clin Invest, 2014 Apr 20; 124(5). PMID: 24743150    Free PMC article.
Highly Cited.
Tim-3 expression and its role in hepatocellular carcinoma.
Feifei Liu, Yanning Liu, Zhi Chen.
J Hematol Oncol, 2018 Oct 13; 11(1). PMID: 30309387    Free PMC article.
Cholangiocarcinoma--controversies and challenges.
Tushar Patel.
Nat Rev Gastroenterol Hepatol, 2011 Apr 05; 8(4). PMID: 21460876    Free PMC article.
Highly Cited. Review.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma.
Kostandinos Sideras, Katharina Biermann, +17 authors, Jaap Kwekkeboom.
Oncoimmunology, 2017 Mar 28; 6(2). PMID: 28344887    Free PMC article.
Highly Cited.
VISTA Regulates the Development of Protective Antitumor Immunity.
Isabelle Le Mercier, Wenna Chen, +5 authors, Li Wang.
Cancer Res, 2014 Apr 03; 74(7). PMID: 24691994    Free PMC article.
Highly Cited.
Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1.
Hui Li, Xiaoqiang Li, +4 authors, Qinghai Ye.
Hepatology, 2017 Jul 22; 66(6). PMID: 28732118
The blockade of immune checkpoints in cancer immunotherapy.
Drew M Pardoll.
Nat Rev Cancer, 2012 Mar 23; 12(4). PMID: 22437870    Free PMC article.
Highly Cited. Review.
Clinical and Genetic Tumor Characteristics of Responding and Non-Responding Patients to PD-1 Inhibition in Hepatocellular Carcinoma.
Stephan Spahn, Daniel Roessler, +13 authors, Michael Bitzer.
Cancers (Basel), 2020 Dec 24; 12(12). PMID: 33353145    Free PMC article.
B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation.
Xiaojie Wang, Jianqiang Hao, +6 authors, Garth L Warnock.
PLoS One, 2012 Jan 13; 7(1). PMID: 22238573    Free PMC article.
PD-L1 expression in extrahepatic cholangiocarcinoma.
Dirk Walter, Eva Herrmann, +4 authors, Sylvia Hartmann.
Histopathology, 2017 Apr 19; 71(3). PMID: 28419539
PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma.
Jacqueline Fontugne, Jérémy Augustin, +8 authors, Julien Calderaro.
Oncotarget, 2017 Apr 28; 8(15). PMID: 28445951    Free PMC article.
Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing.
Chunhong Zheng, Liangtao Zheng, +13 authors, Zemin Zhang.
Cell, 2017 Jun 18; 169(7). PMID: 28622514
Highly Cited.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
Freddie Bray, Jacques Ferlay, +3 authors, Ahmedin Jemal.
CA Cancer J Clin, 2018 Sep 13; 68(6). PMID: 30207593
Highly Cited.
The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.
Robert J Johnston, Laetitia Comps-Agrar, +9 authors, Jane L Grogan.
Cancer Cell, 2014 Dec 04; 26(6). PMID: 25465800
Highly Cited.
Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells.
Jing Li, Younghee Lee, +12 authors, Chen Dong.
Immunity, 2018 Apr 08; 48(4). PMID: 29625896
Highly Cited.
Role of chemokines in hepatocellular carcinoma (Review).
Dongdong Xue, Ya Zheng, +4 authors, Yanhui Peng.
Oncol Rep, 2021 Mar 03; 45(3). PMID: 33650640    Free PMC article.
Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages.
Wenjiang Yan, Xiao Liu, +5 authors, Chunhong Ma.
Gut, 2015 Jan 23; 64(10). PMID: 25608525
Highly Cited.
B7-H3 expression and its correlation with clinicopathologic features, angiogenesis, and prognosis in intrahepatic cholangiocarcinoma.
Rui Cheng, Yongqin Chen, +3 authors, Yanling Chen.
APMIS, 2018 Apr 27; 126(5). PMID: 29696716
Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer.
Junko Matsuzaki, Sacha Gnjatic, +9 authors, Kunle Odunsi.
Proc Natl Acad Sci U S A, 2010 Apr 14; 107(17). PMID: 20385810    Free PMC article.
Highly Cited.
Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy.
A Rotte, J Y Jin, V Lemaire.
Ann Oncol, 2017 Oct 27; 29(1). PMID: 29069302
Highly Cited. Review.
Tim-3 and its role in regulating anti-tumor immunity.
Madhumita Das, Chen Zhu, Vijay K Kuchroo.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258697    Free PMC article.
Highly Cited. Review.
4-1BB Delineates Distinct Activation Status of Exhausted Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma.
Hyung-Don Kim, Seongyeol Park, +15 authors, Su-Hyung Park.
Hepatology, 2019 Jul 30; 71(3). PMID: 31353502    Free PMC article.
A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.
Bruno Sangro, Carlos Gomez-Martin, +11 authors, Jesús Prieto.
J Hepatol, 2013 Mar 08; 59(1). PMID: 23466307
Highly Cited.
Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma.
Hang Li, Ke Wu, +8 authors, Weiping Zou.
Hepatology, 2012 Apr 17; 56(4). PMID: 22505239
Highly Cited.
PD-L1 and PD-1 expression correlate with prognosis in extrahepatic cholangiocarcinoma.
Ke Ma, Xin Wei, +3 authors, Enxiao Li.
Oncol Lett, 2017 Jul 12; 14(1). PMID: 28693161    Free PMC article.
Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial.
Sarah B Goldberg, Scott N Gettinger, +18 authors, Harriet M Kluger.
Lancet Oncol, 2016 Jun 09; 17(7). PMID: 27267608    Free PMC article.
Highly Cited.
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
Dung T Le, Jennifer N Durham, +43 authors, Luis A Diaz.
Science, 2017 Jun 10; 357(6349). PMID: 28596308    Free PMC article.
Highly Cited.
Corrigendum: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.
Yu-Hwa Huang, Chen Zhu, +21 authors, Richard S Blumberg.
Nature, 2016 Mar 17; 536(7616). PMID: 26982724    Free PMC article.
The Function of the HGF/c-Met Axis in Hepatocellular Carcinoma.
Haiyu Wang, Benchen Rao, +6 authors, Zujiang Yu.
Front Cell Dev Biol, 2020 Mar 03; 8. PMID: 32117981    Free PMC article.
Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack.
Chamutal Gur, Yara Ibrahim, +21 authors, Ofer Mandelboim.
Immunity, 2015 Feb 15; 42(2). PMID: 25680274    Free PMC article.
Highly Cited.
Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area.
K Sideras, S J Bots, +8 authors, J Kwekkeboom.
Br J Cancer, 2015 Jun 10; 112(12). PMID: 26057582    Free PMC article.
Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.
Jun Wang, Miguel F Sanmamed, +18 authors, Lieping Chen.
Cell, 2018 Dec 26; 176(1-2). PMID: 30580966    Free PMC article.
Highly Cited.
Immune-checkpoint proteins VISTA and PD-1 nonredundantly regulate murine T-cell responses.
Jun Liu, Ying Yuan, +8 authors, Li Wang.
Proc Natl Acad Sci U S A, 2015 May 13; 112(21). PMID: 25964334    Free PMC article.
Highly Cited.
Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma.
Liang-Qing Dong, Li-Hua Peng, +26 authors, Qiang Gao.
J Hepatol, 2019 Dec 31; 72(5). PMID: 31887370
The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses.
Woong-Kyung Suh, Beata U Gajewska, +21 authors, Tak W Mak.
Nat Immunol, 2003 Aug 20; 4(9). PMID: 12925852
Highly Cited.
Human CD14+ CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma.
Yanmei Han, Zhubo Chen, +9 authors, Xuetao Cao.
Hepatology, 2013 Aug 21; 59(2). PMID: 23960017
Programmed Death-Ligand 1 (PD-L1) Expression Associated with a High Neutrophil/Lymphocyte Ratio in Cholangiocarcinoma
Sakkarn Sangkhamanon, Piangpen Jongpairat, +5 authors, Jarin Chindaprasirt.
Asian Pac J Cancer Prev, 2017 Jul 04; 18(6). PMID: 28670887    Free PMC article.
Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma.
Hae Il Jung, Dongjun Jeong, +7 authors, Moo-Jun Baek.
Cancer Res Treat, 2016 Jul 28; 49(1). PMID: 27456947    Free PMC article.
Highly Cited.
Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma.
Duaa O Khair, Heather J Bax, +22 authors, Sophia N Karagiannis.
Front Immunol, 2019 Apr 04; 10. PMID: 30941125    Free PMC article.
Highly Cited. Review.
KB-68A7.1 Inhibits Hepatocellular Carcinoma Development Through Binding to NSD1 and Suppressing Wnt/β-Catenin Signalling.
Shuhua Zhang, Jianqun Xu, +2 authors, Jun Xiong.
Front Oncol, 2022 Feb 08; 11. PMID: 35127520    Free PMC article.