Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut–liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
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Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
Pawlotsky, J. M. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol. 12, 96–102 (2004).
Trepo, C., Chan, H. L. & Lok, A. Hepatitis B virus infection. Lancet 384, 2053–2063 (2014).
Morgan, T. R., Mandayam, S. & Jamal, M. M. Alcohol and hepatocellular carcinoma. Gastroenterology 127, S87–S96 (2004).
Gao, B. & Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141, 1572–1585 (2011).
Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).
Zhang, D. Y. & Friedman, S. L. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 56, 769–775 (2012).
Clavien, P. A. et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 13, e11–e22 (2012).
Vitale, A. et al. Personalized treatment of patients with very early hepatocellular carcinoma. J. Hepatol. 66, 412–423 (2017).
Forner, A., Reig, M. & Bruix, J. Hepatocellular carcinoma. Lancet 391, 1301–1314 (2018).
Whiteside, T. L., Demaria, S., Rodriguez-Ruiz, M. E., Zarour, H. M. & Melero, I. Emerging opportunities and challenges in cancer immunotherapy. Clin. Cancer Res. 22, 1845–1855 (2016).
Hoos, A. Development of immuno-oncology drugs—from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016).
Cheng, A. L., Hsu, C., Chan, S. L., Choo, S. P. & Kudo, M. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma. J. Hepatol. 72, 307–319 (2020).
Yasuoka, H. et al. Increased both PD-L1 and PD-L2 expressions on monocytes of patients with hepatocellular carcinoma was associated with a poor prognosis. Sci. Rep. 10, 10377 (2020).
Cao, D. et al. Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes. Aging 12, 12187–12205 (2020).
Kurebayashi, Y. et al. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology 68, 1025–1041 (2018).
Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 e814 (2018).
Liu, F. et al. Microenvironment characterization and multi-omics signatures related to prognosis and immunotherapy response of hepatocellular carcinoma. Exp. Hematol. Oncol. 9, 10 (2020).
Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949.e16 (2017).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).
Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).
Heymann, F. & Tacke, F. Immunology in the liver-from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
Kudo, M. 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).
Callahan, M. K., Postow, M. A., Wolchok, J. D. & Targeting, T. Cell co-receptors for cancer therapy. Immunity 44, 1069–1078 (2016).
El-Khoueiry, A. B. 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).
Zhu, A. X. 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).
Sangro, B. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 59, 81–88 (2013).
Wainberg, Z. A. et al. Safety and clinical activity of durvalumab monotherapy in patients with hepatocellular carcinoma (HCC). J. Clin. Oncol. 35, 4071–4071 (2017).
Yau, T. et al. CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann. Oncol. 30, 874–875 (2019).
Finn, R. S. et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J. Clin. Oncol. 38, 193–202 (2020).
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68, 6779–6788 (2008).
Yu, J. H. et al. Platelet-derived growth factor receptor α in hepatocellular carcinoma is a prognostic marker independent of underlying liver cirrhosis. Oncotarget. 8, 39534–39546 (2017).
Zhu, A. X. et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). J. Clin. Oncol. 38, 4519–4519 (2020).
Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).
Hammers, H. J. et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J. Clin. Oncol. 35, 3851–3858 (2017).
Hellmann, M. D. et al. Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
Kelley, R. K. et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J. Clin. Oncol. 35, 4073–4073 (2017).
Kelley, R., Kudo, M. & Harris, W. The novel regimen of tremelimumab in combination with durvalumab provides a favorable safety profile and clinical activity for patients with advanced hepatocellular carcinoma (aHCC). In ESMO World Congress on Gastrointestinal Cancer 2020. July 1-4, 2020; Virtual. Abstract O-6 (Timeline of US FDA, 2020).
Yau, T. et al. Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J. Clin. Oncol. 37, 4012–4012 (2019).
Duffy, A. G. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 66, 545–551 (2017).
June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018).
Zhai, B. et al. A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+hepatocellular carcinoma (r/r GPC3+HCC). J.Clin. Oncol. 35 https://doi.org/10.1200/JCO.2017.35.15_suppl.3049 (2017).
Sun, L. et al. Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma. Tumour Biol. 37, 799–806 (2016).
Yu, X. et al. A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma. J. Clin. Immunol. 34, 194–203 (2014).
Lee, J. H. et al. Sustained efficacy of adjuvant immunotherapy with cytokine-induced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. Cancer Immunol. Immunother. 68, 23–32 (2019).
Tada, F. et al. Phase I/II study of immunotherapy using tumor antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Int. J. Oncol. 41, 1601–1609 (2012).
Iwashita, Y. et al. A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol. Immunother. 52, 155–161 (2003).
El Ansary, M. et al. Immunotherapy by autologous dendritic cell vaccine in patients with advanced HCC. J. Cancer Res. Clin. Oncol. 139, 39–48 (2013).
Nakagawa, H. et al. Association between high-avidity T-cell receptors, induced by α-fetoprotein-derived peptides, and anti-tumor effects in patients with hepatocellular carcinoma. Gastroenterology 152, 1395–1406.e10 (2017).
Sawada, Y. et al. Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival. Clin Cancer Res. 18, 3686–3696 (2012).
Sawada, Y. et al. Programmed death-1 blockade enhances the antitumor effects of peptide vaccine-induced peptide-specific cytotoxic T lymphocytes. Int. J. Oncol. 46, 28–36 (2015).
Greten, T. F. et al. A phase II open label trial evaluating safety and efficacy of a telomerase peptide vaccination in patients with advanced hepatocellular carcinoma. BMC Cancer 10, 209 (2010).
Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19, 329–336 (2013).
de Gramont, A., Faivre, S. & Raymond, E. Novel TGF-beta inhibitors ready for prime time in onco-immunology. Oncoimmunology 6, e1257453 (2017).
Bottcher, J. P., Knolle, P. A. & Stabenow, D. Mechanisms balancing tolerance and immunity in the liver. Dig. Dis. 29, 384–390 (2011).
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).
Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).
Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).
Bald, T., Krummel, M. F., Smyth, M. J. & Barry, K. C. The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies. Nat. Immunol. 21, 835–847 (2020).
Klugewitz, K., Adams, D. H., Emoto, M., Eulenburg, K. & Hamann, A. The composition of intrahepatic lymphocytes: shaped by selective recruitment? Trends Immunol. 25, 590–594 (2004).
Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).
Fehniger, T. A. et al. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell-derived IL-2: a potential new link between adaptive and innate immunity. Blood 101, 3052–3057 (2003).
Ferlazzo, G. et al. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc. Natl Acad. Sci. USA 101, 16606–16611 (2004).
Frey, M. et al. Differential expression and function of L-selectin on CD56bright and CD56dim natural killer cell subsets. J. Immunol. 161, 400–408 (1998).
Sedlmayr, P. et al. Differential phenotypic properties of human peripheral blood CD56dim+ and CD56bright+ natural killer cell subpopulations. Int. Arch. Allergy Immunol. 110, 308–313 (1996).
Tian, Z., Chen, Y. & Gao, B. Natural killer cells in liver disease. Hepatology 57, 1654–1662 (2013).
Collins, P. L. et al. Gene regulatory programs conferring phenotypic identities to human NK cells. Cell 176, 348–360.e312 (2019).
Crinier, A. et al. High-dimensional single-cell analysis identifies organ-specific signatures and conserved NK cell subsets in humans and mice. Immunity 49, 971–986.e975 (2018).
Marquardt, N. et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J. Immunol. 194, 2467–2471 (2015).
Hudspeth, K. et al. Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways. J. Autoimmun. 66, 40–50 (2016).
Stegmann, K. A. et al. CXCR6 marks a novel subset of T-bet(lo)Eomes(hi) natural killer cells residing in human liver. Sci. Rep. 6, 26157 (2016).
Chiossone, L., Dumas, P. Y., Vienne, M. & Vivier, E. Natural killer cells and other innate lymphoid cells in cancer. Nat. Rev. Immunol. 18, 671–688 (2018).
Trinchieri, G. Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989).
Smyth, M. J., Crowe, N. Y. & Godfrey, D. I. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int. Immunol. 13, 459–463 (2001).
Lopez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).
Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).
Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol. 9, 495–502 (2008).
Long, E. O., Kim, H. S., Liu, D., Peterson, M. E. & Rajagopalan, S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu. Rev. Immunol. 31, 227–258 (2013).
Glassner, A. et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab. Investig. 92, 967–977 (2012).
Radaeva, S. et al. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners. Gastroenterology 130, 435–452 (2006).
Ljunggren, H. G. & Karre, K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol. Today 11, 237–244 (1990).
Karre, K. Natural killer cell recognition of missing self. Nat. Immunol. 9, 477–480 (2008).
Cai, L. et al. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin. Immunol. 129, 428–437 (2008).
Chew, V. et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 61, 427–438 (2012).
Tu, Z. et al. TLR-dependent cross talk between human Kupffer cells and NK cells. J. Exp. Med. 205, 233–244 (2008).
Pineiro Fernandez, J., Luddy, K. A., Harmon, C. & O’Farrelly, C. Hepatic tumor microenvironments and effects on NK cell phenotype and function. Int. J. Mol. Sci. 20 https://doi.org/10.3390/ijms20174131 (2019).
Hoechst, B. et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50, 799–807 (2009).
Li, T. et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 318, 154–161 (2012).
Mantovani, S., Oliviero, B., Varchetta, S., Mele, D. & Mondelli, M. U. Natural killer cell responses in hepatocellular carcinoma: implications for novel immunotherapeutic approaches. Cancers 12 https://doi.org/10.3390/cancers12040926 (2020).
Chan, W. K. et al. A CS1-NKG2D bispecific antibody collectively activates cytolytic immune cells against multiple myeloma. Cancer Immunol. Res. 6, 776–787 (2018).
Ferrari de Andrade, L. et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. 359, 1537–1542 (2018).
Vallera, D. A. et al. IL15 trispecific killer engagers (TriKE) make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin. Cancer Res. 22, 3440–3450 (2016).
Davis, Z. B., Vallera, D. A., Miller, J. S. & Felices, M. Natural killer cells unleashed: checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. Semin. Immunol. 31, 64–75 (2017).
Gauthier, L. et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 177, 1701–1713.e1716 (2019).
Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391 e1386 (2015).
Zhang, C. et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front. Immunol. 8, 533 (2017).
Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).
Wang, S. et al. Regulatory innate lymphoid cells control innate intestinal inflammation. Cell 171, 201–216.e218 (2017).
Gao, Y. et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18, 1004–1015 http://www.nature.com/ni/journal/v18/n9/abs/ni.3800.html#supplementary-information (2017).
Hazenberg, M. D. & Spits, H. Human innate lymphoid cells. Blood 124, 700–709 (2014).
Wagner, M. & Koyasu, S. Cancer Immunoediting by Innate Lymphoid Cells. Trends Immunol. 40, 415–430 (2019).
Roderburg, C., Wree, A., Demir, M., Schmelzle, M. & Tacke, F. The role of the innate immune system in the development and treatment of hepatocellular carcinoma. Hepat. Oncol. 7, HEP17 (2020).
Pedroza-Gonzalez, A. et al. Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. Oncoimmunology 4, e1008355 (2015).
Bald, T., Wagner, M., Gao, Y., Koyasu, S. & Smyth, M. J. Hide and seek: plasticity of innate lymphoid cells in cancer. Semin. Immunol. 41, 101273 (2019).
Wagner, M., Moro, K. & Koyasu, S. Plastic heterogeneity of innate lymphoid cells in cancer. Trends Cancer 3, 326–335 (2017).
Bal, S. M., Golebski, K. & Spits, H. Plasticity of innate lymphoid cell subsets. Nat. Rev. Immunol. 20, 552–565 (2020).
Colonna, M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48, 1104–1117 (2018).
Bonne-Annee, S., Bush, M. C. & Nutman, T. B. Differential modulation of human innate lymphoid cell (ILC) subsets by IL-10 and TGF-beta. Sci. Rep. 9, 14305 (2019).
Nabekura, T., Riggan, L., Hildreth, A. D., O’Sullivan, T. E. & Shibuya, A. Type 1 innate lymphoid cells protect mice from acute liver injury via interferon-gamma secretion for upregulating Bcl-xL expression in hepatocytes. Immunity 52, 96–108.e109 (2020).
Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).
Forkel, M. et al. Composition and functionality of the intrahepatic innate lymphoid cell-compartment in human nonfibrotic and fibrotic livers. Eur. J. Immunol. 47, 1280–1294 (2017).
Neumann, K. et al. A proinflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis. J. Immunol. 198, 128–137 (2017).
Steinmann, S. et al. Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4(+) T cells. Sci. Rep. 10, 1071 (2020).
Salimi, M. et al. Activated innate lymphoid cell populations accumulate in human tumour tissues. BMC Cancer 18, 341 (2018).
Jovanovic, I. P. et al. Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int. J. Cancer 134, 1669–1682 (2014).
Moral, J. A. et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature 579, 130–135 (2020).
Matsuda, J. L. et al. Natural killer T cells reactive to a single glycolipid exhibit a highly diverse T cell receptor beta repertoire and small clone size. Proc. Natl Acad. Sci. USA 98, 12636–12641 (2001).
Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).
Lantz, O. & Bendelac, A. An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994).
Kohlgruber, A. C., Donado, C. A., LaMarche, N. M., Brenner, M. B. & Brennan, P. J. Activation strategies for invariant natural killer T cells. Immunogenetics 68, 649–663 (2016).
Hill, T. M., Bezbradica, J. S., Van Kaer, L. & Joyce, S. CD1d‐Restricted Natural Killer T Cells. In eLS, John Wiley & Sons, Ltd (Ed.) (2016). https://doi.org/10.1002/9780470015902.a0020180.pub2.
Brennan, P. J., Brigl, M. & Brenner, M. B. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat. Rev. Immunol. 13, 101–117 (2013).
Bellone, M. et al. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PLoS ONE 5, e8646 (2010).
Cui, J. et al. Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623–1626 (1997).
Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).
Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).
Lee, Y. J. et al. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity 43, 566–578 (2015).
Trobonjaca, Z., Leithauser, F., Moller, P., Schirmbeck, R. & Reimann, J. Activating immunity in the liver. I. Liver dendritic cells (but not hepatocytes) are potent activators of IFN-gamma release by liver NKT cells. J. Immunol. 167, 1413–1422 (2001).
Schmieg, J., Yang, G., Franck, R. W., Van Rooijen, N. & Tsuji, M. Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion. Proc. Natl Acad. Sci. USA 102, 1127–1132 (2005).
Schrumpf, E. et al. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology 62, 1249–1259 (2015).
Syn, W. K. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323–1329 (2012).
Swann, J. B. et al. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113, 6382–6385 (2009).
Bricard, G. et al. Enrichment of human CD4+ V(alpha)24/Vbeta11 invariant NKT cells in intrahepatic malignant tumors. J. Immunol. 182, 5140–5151 (2009).
Wolf, M. J. 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 26, 549–564 (2014).
Syn, W. K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).
Wehr, A. et al. Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J. Immunol. 190, 5226–5236 (2013).
Mossanen, J. C. et al. CXCR6 inhibits hepatocarcinogenesis by promoting natural killer T- and CD4(+) T-cell-dependent control of senescence. Gastroenterology 156, 1877–1889.e1874 (2019).
Ma, C. et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science 360 https://doi.org/10.1126/science.aan5931 (2018).
Kawano, T. et al. Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Valpha14 NKT cells. Proc. Natl Acad. Sci. USA 95, 5690–5693 (1998).
Swann, J. B., Coquet, J. M., Smyth, M. J. & Godfrey, D. I. CD1-restricted T cells and tumor immunity. Curr. Top. Microbiol. Immunol. 314, 293–323 (2007).
Parekh, V. V. et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Investig. 115, 2572–2583 (2005).
Kim, S. et al. Impact of bacteria on the phenotype, functions, and therapeutic activities of invariant NKT cells in mice. J. Clin. Investig. 118, 2301–2315 (2008).
Yamasaki, K. et al. Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin. Immunol. 138, 255–265 (2011).
Kunii, N. et al. Combination therapy of in vitro-expanded natural killer T cells and alpha-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and neck carcinoma. Cancer Sci. 100, 1092–1098 (2009).
Uchida, T. et al. Phase I study of alpha-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. Cancer Immunol. Immunother. 57, 337–345 (2008).
Bollino, D. & Webb, T. J. Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. Transl. Res. 187, 32–43 (2017).
Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).
Le Bourhis, L. et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat. Immunol. 11, 701–708 (2010).
Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).
Corbett, A. J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361–365 (2014).
Reantragoon, R. et al. Antigen-loaded MR1 tetramers define T cell receptor heterogeneity in mucosal-associated invariant T cells. J. Exp. Med. 210, 2305–2320 (2013).
Tilloy, F. et al. An invariant T cell receptor alpha chain defines a novel TAP-independent major histocompatibility complex class Ib-restricted alpha/beta T cell subpopulation in mammals. J. Exp. Med. 189, 1907–1921 (1999).
Gherardin, N. A. et al. Human blood MAIT cell subsets defined using MR1 tetramers. Immunol. Cell Biol. 96, 507–525 (2018).
Kurioka, A., Walker, L. J., Klenerman, P. & Willberg, C. B. MAIT cells: new guardians of the liver. Clin. Transl. Immunol. 5, e98 (2016).
Voillet, V. et al. Human MAIT cells exit peripheral tissues and recirculate via lymph in steady state conditions. JCI Insight 3 https://doi.org/10.1172/jci.insight.98487 (2018).
Kurioka, A. et al. MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets. Mucosal Immunol. 8, 429–440 (2015).
Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).
Duan, M. et al. Activated and exhausted MAIT cells foster disease progression and indicate poor outcome in hepatocellular carcinoma. Clin. Cancer Res. 25, 3304–3316 (2019).
Sundstrom, P. et al. Human mucosa-associated invariant T cells accumulate in colon adenocarcinomas but produce reduced amounts of IFN-gamma. J. Immunol. 195, 3472–3481 (2015).
Melo, A. M. et al. Mucosal-associated invariant T cells display diminished effector capacity in oesophageal adenocarcinoma. Front. Immunol. 10, 1580 (2019).
Ling, L. et al. Circulating and tumor-infiltrating mucosal associated invariant T (MAIT) cells in colorectal cancer patients. Sci. Rep. 6, 20358 (2016).
Zumwalde, N. A. & Gumperz, J. E. In Tumor Microenvironment: Hematopoietic Cells—Part A (ed. Birbrair, A.) 63–77 (Springer International Publishing, 2020).
Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e1316 (2017).
Zabijak, L. et al. Increased tumor infiltration by mucosal-associated invariant T cells correlates with poor survival in colorectal cancer patients. Cancer Immunol. Immunother. 64, 1601–1608 (2015).
Kelly, J. et al. Chronically stimulated human MAIT cells are unexpectedly potent IL-13 producers. Immunol. Cell Biol. 97, 689–699 (2019).
Yan, J. et al. MAIT cells promote tumor initiation, growth, and metastases via tumor MR1. Cancer Discov. 10, 124–141 (2020).
Latham, M. C. Infant feeding in national and international perspective: an examination of the decline in human lactation, and the modern crisis in infant and young child feeding practices. Ann. N. Y. Acad. Sci. 300, 197–209 (1977).
Parker, C. M. et al. Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire. J. Exp. Med. 171, 1597–1612 (1990).
Vasudev, A. et al. Gamma/delta T cell subsets in human aging using the classical alpha/beta T cell model. J. Leukoc. Biol. 96, 647–655 (2014).
Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).
Deseke, M. & Prinz, I. Ligand recognition by the gammadelta TCR and discrimination between homeostasis and stress conditions. Cell Mol. Immunol. 17, 914–924 (2020).
Kabelitz, D., Serrano, R., Kouakanou, L., Peters, C. & Kalyan, S. Cancer immunotherapy with gammadelta T cells: many paths ahead of us. Cell Mol. Immunol. 17, 925–939 (2020).
Wesch, D., Glatzel, A. & Kabelitz, D. Differentiation of resting human peripheral blood gamma delta T cells toward Th1- or Th2-phenotype. Cell. Immunol. 212, 110–117 (2001).
Ness-Schwickerath, K. J., Jin, C. & Morita, C. T. Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vgamma2Vdelta2 T cells. J. Immunol. 184, 7268–7280 (2010).
Caccamo, N. et al. Differentiation, phenotype, and function of interleukin-17-producing human Vgamma9Vdelta2 T cells. Blood 118, 129–138 (2011).
Peters, C., Hasler, R., Wesch, D. & Kabelitz, D. Human Vdelta2 T cells are a major source of interleukin-9. Proc. Natl Acad. Sci. USA 113, 12520–12525 (2016).
Itohara, S. et al. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343, 754–757 (1990).
Goodman, T. & Lefrancois, L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333, 855–858 (1988).
Zhou, Q. H., Wu, F. T., Pang, L. T., Zhang, T. B. & Chen, Z. Role of gammadeltaT cells in liver diseases and its relationship with intestinal microbiota. World J. Gastroenterol. 26, 2559–2569 (2020).
Hunter, S. et al. Human liver infiltrating gammadelta T cells are composed of clonally expanded circulating and tissue-resident populations. J. Hepatol. 69, 654–665 (2018).
Rajoriya, N., Fergusson, J. R., Leithead, J. A. & Klenerman, P. Gamma delta T-Lymphocytes in Hepatitis C and chronic liver disease. Front. Immunol. 5, 400 (2014).
Li, F. et al. The microbiota maintain homeostasis of liver-resident gammadeltaT-17 cells in a lipid antigen/CD1d-dependent manner. Nat. Commun. 7, 13839 (2017).
Wen, L., Peakman, M., Mieli-Vergani, G. & Vergani, D. Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease. Clin. Exp. Immunol. 89, 78–82 (1992).
Wang, X. & Tian, Z. gammadelta T cells in liver diseases. Front. Med. 12, 262–268 (2018).
Zhao, N. et al. Intratumoral gammadelta T-cell infiltrates, CCL4/5 protein expression and survival in patients with hepatocellular carcinoma. Hepatology https://doi.org/10.1002/hep.31412 (2020).
Groh, V. et al. Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc. Natl Acad. Sci. USA 96, 6879–6884 (1999).
Hudspeth, K., Silva-Santos, B. & Mavilio, D. Natural cytotoxicity receptors: broader expression patterns and functions in innate and adaptive immune cells. Front. Immunol. 4, 69 (2013).
Correia, D. V., Lopes, A. & Silva-Santos, B. Tumor cell recognition by gammadelta T lymphocytes: T-cell receptor vs. NK-cell receptors. Oncoimmunology 2, e22892 (2013).
Wrobel, P. et al. Lysis of a broad range of epithelial tumour cells by human gamma delta T cells: involvement of NKG2D ligands and T-cell receptor- versus NKG2D-dependent recognition. Scand. J. Immunol. 66, 320–328 (2007).
Kunzmann, V. & Wilhelm, M. Anti-lymphoma effect of gammadelta T cells. Leuk. Lymphoma 46, 671–680 (2005).
Di Lorenzo, B. et al. Broad cytotoxic targeting of acute myeloid leukemia by polyclonal delta one T cells. Cancer Immunol. Res. 7, 552–558 (2019).
Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
Cordova, A. et al. Characterization of human gammadelta T lymphocytes infiltrating primary malignant melanomas. PLoS ONE 7, e49878 (2012).
Meraviglia, S. et al. Distinctive features of tumor-infiltrating gammadelta T lymphocytes in human colorectal cancer. Oncoimmunology 6, e1347742 (2017).
Cai, X. Y. et al. Low counts of gammadelta T cells in peritumoral liver tissue are related to more frequent recurrence in patients with hepatocellular carcinoma after curative resection. Asian Pac. J. Cancer Prev. 15, 775–780 (2014).
Yi, Y. et al. The functional impairment of HCC-infiltrating gammadelta T cells, partially mediated by regulatory T cells in a TGFbeta- and IL-10-dependent manner. J. Hepatol. 58, 977–983 (2013).
Rei, M., Pennington, D. J. & Silva-Santos, B. The emerging protumor role of gammadelta T lymphocytes: implications for cancer immunotherapy. Cancer Res. 75, 798–802 (2015).
Silva-Santos, B., Serre, K. & Norell, H. Gammadelta T cells in cancer. Nat. Rev. Immunol. 15, 683–691 (2015).
Silva-Santos, B. Promoting angiogenesis within the tumor microenvironment: the secret life of murine lymphoid IL-17-producing gammadelta T cells. Eur. J. Immunol. 40, 1873–1876 (2010).
Jin, C. et al. Commensal microbiota promote lung cancer development via gammadelta T cells. Cell 176, 998–1013.e1016 (2019).
Kong, X., Sun, R., Chen, Y., Wei, H. & Tian, Z. gammadeltaT cells drive myeloid-derived suppressor cell-mediated CD8+ T cell exhaustion in hepatitis B virus-induced immunotolerance. J. Immunol. 193, 1645–1653 (2014).
Wu, P. et al. gammadeltaT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer. Immunity 40, 785–800 (2014).
Ma, S. et al. IL-17A produced by gammadelta T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. 74, 1969–1982 (2014).
Wilhelm, M. et al. Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 102, 200–206 (2003).
Kobayashi, H. et al. Safety profile and anti-tumor effects of adoptive immunotherapy using gamma-delta T cells against advanced renal cell carcinoma: a pilot study. Cancer Immunol. Immunother. 56, 469–476 (2007).
Nicol, A. J. et al. Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours. Br. J. Cancer 105, 778–786 (2011).
Hoeres, T., Smetak, M., Pretscher, D. & Wilhelm, M. Improving the efficiency of Vγ9Vδ2 T-cell immunotherapy in cancer. Front. Immunol. 9, 800 (2018).
Nussbaumer, O. & Koslowski, M. The emerging role of γδ T cells in cancer immunotherapy. Immuno-Oncol. Technol. 1, 3–10 (2019).
Sebestyen, Z., Prinz, I., Dechanet-Merville, J., Silva-Santos, B. & Kuball, J. Translating gammadelta (gammadelta) T cells and their receptors into cancer cell therapies. Nat. Rev. Drug Discov. 19, 169–184 (2020).
Zhao, Y., Niu, C. & Cui, J. Gamma-delta (gammadelta) T cells: friend or foe in cancer development? J. Transl. Med. 16, 3 (2018).
Rozenbaum, M. et al. Gamma-delta CAR-T cells show CAR-directed and independent activity against leukemia. Front. Immunol. 11, 1347 (2020).
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).
Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).
Kiziltas, S. Toll-like receptors in pathophysiology of liver diseases. World J. Hepatol. 8, 1354–1369 (2016).
Benacerraf, B., Sebestyen, M. M. & Schlossman, S. A quantitative study of the kinetics of blood clearance of P32-labelled Escherichia coli and Staphylococci by the reticuloendothelial system. J. Exp. Med. 110, 27–48 (1959).
Fox, E. S., Thomas, P. & Broitman, S. A. Clearance of gut-derived endotoxins by the liver. Release and modification of 3H, 14C-lipopolysaccharide by isolated rat Kupffer cells. Gastroenterology 96, 456–461 (1989).
Gregory, S. H. & Wing, E. J. Neutrophil–Kupffer-cell interaction in host defenses to systemic infections. Immunol. Today 19, 507–510 (1998).
Li, P., He, K., Li, J., Liu, Z. & Gong, J. The role of Kupffer cells in hepatic diseases. Mol. Immunol. 85, 222–229 (2017).
Seki, E. et al. Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J. Immunol. 166, 2651–2657 (2001).
Kopydlowski, K. M. et al. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. J. Immunol. 163, 1537–1544 (1999).
Knolle, P. et al. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22, 226–229 (1995).
Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).
Mossanen, J. C. et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 64, 1667–1682 (2016).
Dal-Secco, D. et al. A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury. J. Exp. Med. 212, 447–456 (2015).
Mencin, A., Kluwe, J. & Schwabe, R. F. Toll-like receptors as targets in chronic liver diseases. Gut 58, 704–720 (2009).
Bishayee, A. In Inflammation and Cancer (eds. Aggarwal, B. B., Sung, B. & Gupta, S. C.) 401–435 (Springer Basel, 2014).
Heymann, F. et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62, 279–291 (2015).
Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).
Koh, M. Y. et al. A new HIF-1alpha/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice. Hepatology 63, 1576–1591 (2016).
Malehmir, M. et al. Platelet GPIbalpha is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat. Med. 25, 641–655 (2019).
Ding, T. et al. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum. Pathol. 40, 381–389 (2009).
Yeung, O. W. et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J. Hepatol. 62, 607–616 (2015).
Wan, S. et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393–1404 (2014).
Li, X. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66, 157–167 (2017).
Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).
Wu, K., Kryczek, I., Chen, L., Zou, W. & Welling, T. H. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res. 69, 8067–8075 (2009).
Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Investig. 125, 3356–3364 (2015).
Hoechst, B. et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology 135, 234–243 (2008).
Wan, S., Kuo, N., Kryczek, I., Zou, W. & Welling, T. H. Myeloid cells in hepatocellular carcinoma. Hepatology 62, 1304–1312 (2015).
Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
Zhang, Q. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829–845.e820 (2019).
Yao, W. et al. A natural CCR2 antagonist relieves tumor-associated macrophage-mediated immunosuppression to produce a therapeutic effect for liver cancer. EBioMedicine 22, 58–67 (2017).
Yu, S. J. et al. Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma. J. Hepatol. 70, 449–457 (2019).
Forbes, S. J., Gupta, S. & Dhawan, A. Cell therapy for liver disease: from liver transplantation to cell factory. J. Hepatol. 62, S157–S169 (2015).
Thomas, J. A. et al. Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology 53, 2003–2015 (2011).
ElTanbouly, M. A. et al. VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance. Science 367 https://doi.org/10.1126/science.aay0524 (2020).
ElTanbouly, M. A., Croteau, W., Noelle, R. J. & Lines, J. L. VISTA: a novel immunotherapy target for normalizing innate and adaptive immunity. Semin. Immunol. 42, 101308 (2019).
Zhang, M. et al. VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma. BMC Cancer 18, 511 (2018).
Nakayama, M. Antigen presentation by MHC-dressed cells. Front. Immunol. 5, 672 (2014).
Thomson, A. W. & Knolle, P. A. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).
Matta, B. M., Castellaneta, A. & Thomson, A. W. Tolerogenic plasmacytoid DC. Eur. J. Immunol. 40, 2667–2676 (2010).
Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).
Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).
Salmon, H. 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).
Sanchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79 (2016).
Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy. Cancer Cell 31, 711–723.e714 (2017).
Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018).
Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 e1014 (2018).
Cheng, J. T. et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis 5, e198 (2016).
Ormandy, L. A. et al. Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J. Gastroenterol. 12, 3275–3282 (2006).
Butterfield, L. H. et al. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin. Cancer Res. 12, 2817–2825 (2006).
Lee, J. H. et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology 6, e1328335 (2017).
Palmer, D. H. et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49, 124–132 (2009).
Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).
Saxena, M. & Bhardwaj, N. Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr. Opin. Immunol. 47, 35–43 (2017).
Chi, H. et al. Anti-tumor activity of Toll-like receptor 7 agonists. Front. Pharmacol. 8, 304 (2017).
Kyi, C. et al. Therapeutic immune modulation against solid cancers with intratumoral poly-ICLC: a pilot trial. Clin. Cancer Res. 24, 4937–4948 (2018).
Sahin, U. & Tureci, O. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).
Nemeth, T., Sperandio, M. & Mocsai, A. Neutrophils as emerging therapeutic targets. Nat. Rev. Drug Discov. 19, 253–275 (2020).
Shaul, M. E. & Fridlender, Z. G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 16, 601–620 (2019).
Chee, D. O., Townsend, C. M. Jr., Galbraith, M. A., Eilber, F. R. & Morton, D. L. Selective reduction of human tumor cell populations by human granulocytes in vitro. Cancer Res. 38, 4534–4539 (1978).
Gerrard, T. L., Cohen, D. J. & Kaplan, A. M. Human neutrophil-mediated cytotoxicity to tumor cells. J. Natl Cancer Inst. 66, 483–488 (1981).
Cameron, D. J. A comparison of the cytotoxic potential in polymorphonuclear leukocytes obtained from normal donors and cancer patients. Clin. Immunol. Immunopathol. 28, 115–124 (1983).
Zhou, S. L. et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 150, 1646–1658.e1617 (2016).
Wang, T. T. et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut 66, 1900–1911 (2017).
Cheng, Y. et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 9, 422 (2018).
Gao, Q. et al. CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res. 72, 3546–3556 (2012).
Zhou, S. L. et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56, 2242–2254 (2012).
Lin, G. et al. Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma. Oncotarget 7, 50963–50971 (2016).
Terashima, T. et al. Blood neutrophil to lymphocyte ratio as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy. Hepatol. Res. 45, 949–959 (2015).
Wang, Y. et al. Circulating neutrophils predict poor survival for HCC and promote HCC progression through p53 and STAT3 signaling pathway. J. Cancer 11, 3736–3744 (2020).
Shen, M. et al. Tumor-associated neutrophils as a new prognostic factor in cancer: a systematic review and meta-analysis. PLoS ONE 9, e98259 (2014).
Li, Y. W. et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J. Hepatol. 54, 497–505 (2011).
Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-020-0306-5 (2020).
van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8(+) T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20, 218–232 (2020).
O’Donnell, J. S., Teng, M. W. L. & Smyth, M. J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 16, 151–167 (2019).
Prieto, J., Melero, I. & Sangro, B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 12, 681–700 (2015).
Lai, C. L., Wu, P. C., Chan, G. C., Lok, A. S. & Lin, H. J. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 62, 479–483 (1988).
Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017).
Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).
Zhu, A. X. et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 282–296 (2019).
Yau, T. et al. LBA38_PRCheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann. Oncol. 30 https://doi.org/10.1093/annonc/mdz394.029 (2019).
Qin, S. et al. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol. 15, 1811–1822 (2019).
Jimenez Exposito, M. J. et al. CA209-9DX: phase III, randomized, double-blind study of adjuvant nivolumab vs placebo for patients with hepatocellular carcinoma (HCC) at high risk of recurrence after curative resection or ablation. Ann. Oncol. 29, ix65 (2018).
Abou-Alfa, G. K. et al. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. 36, TPS4144 https://doi.org/10.1200/JCO.2018.36.15_suppl.TPS4144 (2018).
Finn, R. S. et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J. Clin. Oncol. 38, 2960–2970 (2020).
Kelley, R. K. et al. Phase 3 (COSMIC-312) study of cabozantinib (C) in combination with atezolizumab (A) versus sorafenib (S) in patients (pts) with advanced hepatocellular carcinoma (aHCC) who have not received previous systemic anticancer therapy. J. Clin. Oncol. 37, TPS4157–TPS4157 (2019).
Knox, J. et al. A phase 3 study of durvalumab with or without bevacizumab as adjuvant therapy in patients with hepatocellular carcinoma (HCC) who are at high risk of recurrence after curative hepatic resection. Ann. Oncol. 30, iv51 (2019).
Sangro, B. et al. P-347 A phase 3, randomized, double-blind, placebo-controlled study of transarterial chemoembolization combined with durvalumab or durvalumab plus bevacizumab therapy in patients with locoregional hepatocellular carcinoma: EMERALD-1. Ann. Oncol. 31, S202–S203 (2020).
Cichocki, F. et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 77, 5664–5675 (2017).
Takayama, T. et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356, 802–807 (2000).
Rizell, M. et al. Phase 1 trial with the cell-based immune primer ilixadencel, alone, and combined with sorafenib, in advanced hepatocellular carcinoma. Front. Oncol. 9, 19 (2019).
Di Blasi, D. et al. Unique T-cell populations define immune-inflamed hepatocellular carcinoma. Cell Mol. Gastroenterol. Hepatol. 9, 195–218 (2020).
Zhang, Q. et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut 68, 2019–2031 (2019).
Ouyang, F. Z. et al. Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma. Nat. Commun. 7, 13453 (2016).
Li, X. et al. Neutrophil count is associated with myeloid derived suppressor cell level and presents prognostic value of for hepatocellular carcinoma patients. Oncotarget 8, 24380–24388 (2017).
Personeni, N. et al. Prognostic value of the neutrophil-to-lymphocyte ratio in the ARQ 197-215 second-line study for advanced hepatocellular carcinoma. Oncotarget 8, 14408–14415 (2017).
Kuang, D. M. et al. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J. Hepatol. 54, 948–955 (2011).
T.F.G. was supported by the Intramural Research Program of the NIH, NCI (ZIA BC 011345).
The authors declare no competing interests.
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Ruf, B., Heinrich, B. & Greten, T.F. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol 18, 112–127 (2021). https://doi.org/10.1038/s41423-020-00572-w
- innate immunity
- tumor microenvironment
Cellular & Molecular Immunology (2021)
Cellular & Molecular Immunology (2021)