Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. 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).

    PubMed  Google Scholar 

  2. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).

    PubMed  Google Scholar 

  3. Pawlotsky, J. M. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol. 12, 96–102 (2004).

    CAS  PubMed  Google Scholar 

  4. Trepo, C., Chan, H. L. & Lok, A. Hepatitis B virus infection. Lancet 384, 2053–2063 (2014).

    CAS  PubMed  Google Scholar 

  5. Morgan, T. R., Mandayam, S. & Jamal, M. M. Alcohol and hepatocellular carcinoma. Gastroenterology 127, S87–S96 (2004).

    CAS  PubMed  Google Scholar 

  6. Gao, B. & Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141, 1572–1585 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    PubMed  Google Scholar 

  8. Zhang, D. Y. & Friedman, S. L. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 56, 769–775 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Clavien, P. A. et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 13, e11–e22 (2012).

    PubMed  Google Scholar 

  10. Vitale, A. et al. Personalized treatment of patients with very early hepatocellular carcinoma. J. Hepatol. 66, 412–423 (2017).

    PubMed  Google Scholar 

  11. Forner, A., Reig, M. & Bruix, J. Hepatocellular carcinoma. Lancet 391, 1301–1314 (2018).

    PubMed  Google Scholar 

  12. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hoos, A. Development of immuno-oncology drugs—from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016).

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

  15. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Cao, D. et al. Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes. Aging 12, 12187–12205 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    CAS  PubMed  Google Scholar 

  18. Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 e814 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949.e16 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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).

    CAS  PubMed  Google Scholar 

  24. Heymann, F. & Tacke, F. Immunology in the liver-from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).

    CAS  PubMed  Google Scholar 

  25. Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).

    CAS  PubMed  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

  27. Callahan, M. K., Postow, M. A., Wolchok, J. D. & Targeting, T. Cell co-receptors for cancer therapy. Immunity 44, 1069–1078 (2016).

    CAS  PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. 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).

    Google Scholar 

  32. 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).

    Google Scholar 

  33. 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).

    CAS  PubMed  Google Scholar 

  34. Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).

    CAS  PubMed  Google Scholar 

  35. Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68, 6779–6788 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 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).

    PubMed  PubMed Central  Google Scholar 

  37. 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).

    Google Scholar 

  38. Larkin, J. et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 381, 1535–1546 (2019).

    CAS  PubMed  Google Scholar 

  39. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Google Scholar 

  42. 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).

  43. 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).

    Google Scholar 

  44. Duffy, A. G. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 66, 545–551 (2017).

    CAS  PubMed  Google Scholar 

  45. 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).

    CAS  PubMed  Google Scholar 

  46. 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).

  47. 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).

    CAS  PubMed  Google Scholar 

  48. 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).

    CAS  PubMed  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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).

    CAS  PubMed  Google Scholar 

  53. 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).

    CAS  PubMed  Google Scholar 

  54. 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).

    CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. 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).

    PubMed  PubMed Central  Google Scholar 

  57. Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19, 329–336 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. de Gramont, A., Faivre, S. & Raymond, E. Novel TGF-beta inhibitors ready for prime time in onco-immunology. Oncoimmunology 6, e1257453 (2017).

    PubMed  Google Scholar 

  59. Bottcher, J. P., Knolle, P. A. & Stabenow, D. Mechanisms balancing tolerance and immunity in the liver. Dig. Dis. 29, 384–390 (2011).

    PubMed  Google Scholar 

  60. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).

    CAS  PubMed  Google Scholar 

  63. Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).

    CAS  PubMed  Google Scholar 

  64. 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).

    CAS  PubMed  Google Scholar 

  65. 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).

    CAS  PubMed  Google Scholar 

  66. Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    CAS  PubMed  Google Scholar 

  68. 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).

    CAS  PubMed  Google Scholar 

  69. 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).

    CAS  PubMed  Google Scholar 

  70. 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).

    CAS  PubMed  Google Scholar 

  71. Tian, Z., Chen, Y. & Gao, B. Natural killer cells in liver disease. Hepatology 57, 1654–1662 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Collins, P. L. et al. Gene regulatory programs conferring phenotypic identities to human NK cells. Cell 176, 348–360.e312 (2019).

    CAS  PubMed  Google Scholar 

  73. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Marquardt, N. et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J. Immunol. 194, 2467–2471 (2015).

    CAS  PubMed  Google Scholar 

  75. 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).

    CAS  PubMed  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 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).

    CAS  PubMed  Google Scholar 

  78. Trinchieri, G. Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

  80. Lopez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).

    CAS  PubMed  Google Scholar 

  81. Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).

    CAS  PubMed  Google Scholar 

  82. Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol. 9, 495–502 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  Google Scholar 

  84. 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).

    PubMed  Google Scholar 

  85. 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).

    CAS  PubMed  Google Scholar 

  86. Ljunggren, H. G. & Karre, K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol. Today 11, 237–244 (1990).

    CAS  PubMed  Google Scholar 

  87. Karre, K. Natural killer cell recognition of missing self. Nat. Immunol. 9, 477–480 (2008).

    PubMed  Google Scholar 

  88. 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).

    CAS  PubMed  Google Scholar 

  89. 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).

    CAS  PubMed  Google Scholar 

  90. Tu, Z. et al. TLR-dependent cross talk between human Kupffer cells and NK cells. J. Exp. Med. 205, 233–244 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

  92. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Li, T. et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 318, 154–161 (2012).

    CAS  PubMed  Google Scholar 

  94. 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).

  95. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ferrari de Andrade, L. et al. Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity. 359, 1537–1542 (2018).

  97. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Gauthier, L. et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 177, 1701–1713.e1716 (2019).

    CAS  PubMed  Google Scholar 

  100. Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391 e1386 (2015).

    CAS  PubMed  Google Scholar 

  101. 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).

    PubMed  PubMed Central  Google Scholar 

  102. Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).

    CAS  PubMed  Google Scholar 

  103. Wang, S. et al. Regulatory innate lymphoid cells control innate intestinal inflammation. Cell 171, 201–216.e218 (2017).

    CAS  PubMed  Google Scholar 

  104. 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).

    CAS  PubMed  Google Scholar 

  105. Hazenberg, M. D. & Spits, H. Human innate lymphoid cells. Blood 124, 700–709 (2014).

    CAS  PubMed  Google Scholar 

  106. Wagner, M. & Koyasu, S. Cancer Immunoediting by Innate Lymphoid Cells. Trends Immunol. 40, 415–430 (2019).

    CAS  PubMed  Google Scholar 

  107. 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).

    PubMed  PubMed Central  Google Scholar 

  108. Pedroza-Gonzalez, A. et al. Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. Oncoimmunology 4, e1008355 (2015).

    PubMed  PubMed Central  Google Scholar 

  109. 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).

    PubMed  Google Scholar 

  110. Wagner, M., Moro, K. & Koyasu, S. Plastic heterogeneity of innate lymphoid cells in cancer. Trends Cancer 3, 326–335 (2017).

    CAS  PubMed  Google Scholar 

  111. Bal, S. M., Golebski, K. & Spits, H. Plasticity of innate lymphoid cell subsets. Nat. Rev. Immunol. 20, 552–565 (2020).

    CAS  PubMed  Google Scholar 

  112. Colonna, M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48, 1104–1117 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 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).

    PubMed  PubMed Central  Google Scholar 

  114. 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).

    CAS  PubMed  Google Scholar 

  115. Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    CAS  PubMed  Google Scholar 

  117. Neumann, K. et al. A proinflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis. J. Immunol. 198, 128–137 (2017).

    CAS  PubMed  Google Scholar 

  118. Steinmann, S. et al. Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4(+) T cells. Sci. Rep. 10, 1071 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Salimi, M. et al. Activated innate lymphoid cell populations accumulate in human tumour tissues. BMC Cancer 18, 341 (2018).

    PubMed  PubMed Central  Google Scholar 

  120. 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).

    CAS  PubMed  Google Scholar 

  121. Moral, J. A. et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature 579, 130–135 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    CAS  PubMed  Google Scholar 

  123. Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).

    CAS  PubMed  Google Scholar 

  124. 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).

    CAS  PubMed  Google Scholar 

  125. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 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.

  127. 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).

    CAS  PubMed  Google Scholar 

  128. Bellone, M. et al. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PLoS ONE 5, e8646 (2010).

    PubMed  PubMed Central  Google Scholar 

  129. Cui, J. et al. Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623–1626 (1997).

    CAS  PubMed  Google Scholar 

  130. Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).

    CAS  PubMed  Google Scholar 

  131. Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).

    CAS  PubMed  Google Scholar 

  132. Lee, Y. J. et al. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity 43, 566–578 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 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).

    CAS  PubMed  Google Scholar 

  134. 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).

    CAS  PubMed  Google Scholar 

  135. Schrumpf, E. et al. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology 62, 1249–1259 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Syn, W. K. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323–1329 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Swann, J. B. et al. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113, 6382–6385 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 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).

    CAS  PubMed  Google Scholar 

  139. 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).

    CAS  PubMed  Google Scholar 

  140. Syn, W. K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Wehr, A. et al. Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J. Immunol. 190, 5226–5236 (2013).

    CAS  PubMed  Google Scholar 

  142. 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).

    PubMed  Google Scholar 

  143. 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).

  144. 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).

    CAS  PubMed  Google Scholar 

  145. 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).

    CAS  PubMed  Google Scholar 

  146. Parekh, V. V. et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Investig. 115, 2572–2583 (2005).

    CAS  PubMed  Google Scholar 

  147. 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).

    CAS  PubMed  Google Scholar 

  148. 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).

    CAS  PubMed  Google Scholar 

  149. 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).

    CAS  PubMed  Google Scholar 

  150. 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).

    CAS  PubMed  Google Scholar 

  151. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).

    CAS  PubMed  Google Scholar 

  153. Le Bourhis, L. et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat. Immunol. 11, 701–708 (2010).

    PubMed  Google Scholar 

  154. Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).

    CAS  PubMed  Google Scholar 

  155. Corbett, A. J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361–365 (2014).

    CAS  PubMed  Google Scholar 

  156. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Gherardin, N. A. et al. Human blood MAIT cell subsets defined using MR1 tetramers. Immunol. Cell Biol. 96, 507–525 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Kurioka, A., Walker, L. J., Klenerman, P. & Willberg, C. B. MAIT cells: new guardians of the liver. Clin. Transl. Immunol. 5, e98 (2016).

    Google Scholar 

  160. 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).

  161. Kurioka, A. et al. MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets. Mucosal Immunol. 8, 429–440 (2015).

    CAS  PubMed  Google Scholar 

  162. Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).

    CAS  PubMed  Google Scholar 

  163. 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).

    PubMed  Google Scholar 

  164. 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).

    PubMed  Google Scholar 

  165. Melo, A. M. et al. Mucosal-associated invariant T cells display diminished effector capacity in oesophageal adenocarcinoma. Front. Immunol. 10, 1580 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Ling, L. et al. Circulating and tumor-infiltrating mucosal associated invariant T (MAIT) cells in colorectal cancer patients. Sci. Rep. 6, 20358 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Zumwalde, N. A. & Gumperz, J. E. In Tumor Microenvironment: Hematopoietic Cells—Part A (ed. Birbrair, A.) 63–77 (Springer International Publishing, 2020).

  168. Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e1316 (2017).

    CAS  PubMed  Google Scholar 

  169. 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).

    CAS  PubMed  Google Scholar 

  170. Kelly, J. et al. Chronically stimulated human MAIT cells are unexpectedly potent IL-13 producers. Immunol. Cell Biol. 97, 689–699 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Yan, J. et al. MAIT cells promote tumor initiation, growth, and metastases via tumor MR1. Cancer Discov. 10, 124–141 (2020).

    CAS  PubMed  Google Scholar 

  172. 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).

    CAS  PubMed  Google Scholar 

  173. Parker, C. M. et al. Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire. J. Exp. Med. 171, 1597–1612 (1990).

    CAS  PubMed  Google Scholar 

  174. 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).

    PubMed  Google Scholar 

  175. Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Deseke, M. & Prinz, I. Ligand recognition by the gammadelta TCR and discrimination between homeostasis and stress conditions. Cell Mol. Immunol. 17, 914–924 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 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).

    CAS  PubMed  Google Scholar 

  179. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Caccamo, N. et al. Differentiation, phenotype, and function of interleukin-17-producing human Vgamma9Vdelta2 T cells. Blood 118, 129–138 (2011).

    CAS  PubMed  Google Scholar 

  181. 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).

    CAS  PubMed  Google Scholar 

  182. Itohara, S. et al. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343, 754–757 (1990).

    CAS  PubMed  Google Scholar 

  183. Goodman, T. & Lefrancois, L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333, 855–858 (1988).

    CAS  PubMed  Google Scholar 

  184. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 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).

    PubMed  PubMed Central  Google Scholar 

  187. 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).

    PubMed  Google Scholar 

  188. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Wang, X. & Tian, Z. gammadelta T cells in liver diseases. Front. Med. 12, 262–268 (2018).

    CAS  PubMed  Google Scholar 

  190. 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).

  191. 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).

    CAS  PubMed  Google Scholar 

  192. 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).

    PubMed  PubMed Central  Google Scholar 

  193. 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).

    PubMed  PubMed Central  Google Scholar 

  194. 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).

    CAS  PubMed  Google Scholar 

  195. Kunzmann, V. & Wilhelm, M. Anti-lymphoma effect of gammadelta T cells. Leuk. Lymphoma 46, 671–680 (2005).

    CAS  PubMed  Google Scholar 

  196. 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).

    PubMed  Google Scholar 

  197. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Cordova, A. et al. Characterization of human gammadelta T lymphocytes infiltrating primary malignant melanomas. PLoS ONE 7, e49878 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Meraviglia, S. et al. Distinctive features of tumor-infiltrating gammadelta T lymphocytes in human colorectal cancer. Oncoimmunology 6, e1347742 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 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).

    PubMed  Google Scholar 

  201. 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).

    CAS  PubMed  Google Scholar 

  202. 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).

    CAS  PubMed  Google Scholar 

  203. Silva-Santos, B., Serre, K. & Norell, H. Gammadelta T cells in cancer. Nat. Rev. Immunol. 15, 683–691 (2015).

    CAS  PubMed  Google Scholar 

  204. 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).

    CAS  PubMed  Google Scholar 

  205. Jin, C. et al. Commensal microbiota promote lung cancer development via gammadelta T cells. Cell 176, 998–1013.e1016 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. 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).

    CAS  PubMed  Google Scholar 

  207. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Ma, S. et al. IL-17A produced by gammadelta T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. 74, 1969–1982 (2014).

    CAS  PubMed  Google Scholar 

  209. Wilhelm, M. et al. Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 102, 200–206 (2003).

    CAS  PubMed  Google Scholar 

  210. 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).

    CAS  PubMed  Google Scholar 

  211. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Hoeres, T., Smetak, M., Pretscher, D. & Wilhelm, M. Improving the efficiency of Vγ9Vδ2 T-cell immunotherapy in cancer. Front. Immunol. 9, 800 (2018).

    PubMed  PubMed Central  Google Scholar 

  213. Nussbaumer, O. & Koslowski, M. The emerging role of γδ T cells in cancer immunotherapy. Immuno-Oncol. Technol. 1, 3–10 (2019).

    Google Scholar 

  214. 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).

    CAS  PubMed  Google Scholar 

  215. Zhao, Y., Niu, C. & Cui, J. Gamma-delta (gammadelta) T cells: friend or foe in cancer development? J. Transl. Med. 16, 3 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Rozenbaum, M. et al. Gamma-delta CAR-T cells show CAR-directed and independent activity against leukemia. Front. Immunol. 11, 1347 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).

    PubMed  Google Scholar 

  218. Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).

    CAS  PubMed  Google Scholar 

  219. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Kiziltas, S. Toll-like receptors in pathophysiology of liver diseases. World J. Hepatol. 8, 1354–1369 (2016).

    PubMed  PubMed Central  Google Scholar 

  221. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 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).

    CAS  PubMed  Google Scholar 

  223. Gregory, S. H. & Wing, E. J. Neutrophil–Kupffer-cell interaction in host defenses to systemic infections. Immunol. Today 19, 507–510 (1998).

    CAS  PubMed  Google Scholar 

  224. Li, P., He, K., Li, J., Liu, Z. & Gong, J. The role of Kupffer cells in hepatic diseases. Mol. Immunol. 85, 222–229 (2017).

    CAS  PubMed  Google Scholar 

  225. 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).

    CAS  PubMed  Google Scholar 

  226. Kopydlowski, K. M. et al. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. J. Immunol. 163, 1537–1544 (1999).

    CAS  PubMed  Google Scholar 

  227. Knolle, P. et al. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22, 226–229 (1995).

    CAS  PubMed  Google Scholar 

  228. Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).

    CAS  PubMed  Google Scholar 

  229. 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).

    CAS  PubMed  Google Scholar 

  230. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Mencin, A., Kluwe, J. & Schwabe, R. F. Toll-like receptors as targets in chronic liver diseases. Gut 58, 704–720 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Bishayee, A. In Inflammation and Cancer (eds. Aggarwal, B. B., Sung, B. & Gupta, S. C.) 401–435 (Springer Basel, 2014).

  233. Heymann, F. et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62, 279–291 (2015).

    CAS  PubMed  Google Scholar 

  234. 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).

    CAS  PubMed  Google Scholar 

  235. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 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).

    CAS  PubMed  Google Scholar 

  237. 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).

    CAS  PubMed  Google Scholar 

  238. Yeung, O. W. et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J. Hepatol. 62, 607–616 (2015).

    CAS  PubMed  Google Scholar 

  239. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 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).

    CAS  PubMed  Google Scholar 

  241. Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).

    CAS  PubMed  Google Scholar 

  242. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Investig. 125, 3356–3364 (2015).

    PubMed  Google Scholar 

  244. 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).

    CAS  PubMed  Google Scholar 

  245. Wan, S., Kuo, N., Kryczek, I., Zou, W. & Welling, T. H. Myeloid cells in hepatocellular carcinoma. Hepatology 62, 1304–1312 (2015).

    PubMed  PubMed Central  Google Scholar 

  246. Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).

    CAS  PubMed  Google Scholar 

  247. Zhang, Q. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829–845.e820 (2019).

    CAS  PubMed  Google Scholar 

  248. 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).

    PubMed  PubMed Central  Google Scholar 

  249. 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).

    CAS  PubMed  Google Scholar 

  250. Forbes, S. J., Gupta, S. & Dhawan, A. Cell therapy for liver disease: from liver transplantation to cell factory. J. Hepatol. 62, S157–S169 (2015).

    CAS  PubMed  Google Scholar 

  251. 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).

    CAS  PubMed  Google Scholar 

  252. 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).

  253. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. 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).

    PubMed  PubMed Central  Google Scholar 

  255. Nakayama, M. Antigen presentation by MHC-dressed cells. Front. Immunol. 5, 672 (2014).

    PubMed  Google Scholar 

  256. Thomson, A. W. & Knolle, P. A. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).

    CAS  PubMed  Google Scholar 

  257. Matta, B. M., Castellaneta, A. & Thomson, A. W. Tolerogenic plasmacytoid DC. Eur. J. Immunol. 40, 2667–2676 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

  260. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. 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).

    CAS  PubMed  Google Scholar 

  262. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  266. Ormandy, L. A. et al. Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J. Gastroenterol. 12, 3275–3282 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  267. 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).

    CAS  PubMed  Google Scholar 

  268. Lee, J. H. et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology 6, e1328335 (2017).

    PubMed  PubMed Central  Google Scholar 

  269. 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).

    PubMed  Google Scholar 

  270. 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).

    CAS  PubMed  Google Scholar 

  271. Saxena, M. & Bhardwaj, N. Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr. Opin. Immunol. 47, 35–43 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Chi, H. et al. Anti-tumor activity of Toll-like receptor 7 agonists. Front. Pharmacol. 8, 304 (2017).

    PubMed  PubMed Central  Google Scholar 

  273. Kyi, C. et al. Therapeutic immune modulation against solid cancers with intratumoral poly-ICLC: a pilot trial. Clin. Cancer Res. 24, 4937–4948 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. Sahin, U. & Tureci, O. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).

    CAS  PubMed  Google Scholar 

  275. Nemeth, T., Sperandio, M. & Mocsai, A. Neutrophils as emerging therapeutic targets. Nat. Rev. Drug Discov. 19, 253–275 (2020).

    CAS  PubMed  Google Scholar 

  276. Shaul, M. E. & Fridlender, Z. G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 16, 601–620 (2019).

    PubMed  Google Scholar 

  277. 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).

    CAS  PubMed  Google Scholar 

  278. Gerrard, T. L., Cohen, D. J. & Kaplan, A. M. Human neutrophil-mediated cytotoxicity to tumor cells. J. Natl Cancer Inst. 66, 483–488 (1981).

    CAS  PubMed  Google Scholar 

  279. 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).

    CAS  PubMed  Google Scholar 

  280. 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).

    CAS  PubMed  Google Scholar 

  281. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  282. 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).

    PubMed  PubMed Central  Google Scholar 

  283. 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).

    CAS  PubMed  Google Scholar 

  284. Zhou, S. L. et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56, 2242–2254 (2012).

    CAS  PubMed  Google Scholar 

  285. 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).

    PubMed  PubMed Central  Google Scholar 

  286. 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).

    CAS  PubMed  Google Scholar 

  287. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. 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).

    PubMed  PubMed Central  Google Scholar 

  289. Li, Y. W. et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J. Hepatol. 54, 497–505 (2011).

    PubMed  Google Scholar 

  290. 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).

  291. 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).

    PubMed  PubMed Central  Google Scholar 

  292. 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).

    PubMed  Google Scholar 

  293. Prieto, J., Melero, I. & Sangro, B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 12, 681–700 (2015).

    CAS  PubMed  Google Scholar 

  294. 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).

    CAS  PubMed  Google Scholar 

  295. 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).

    CAS  PubMed  Google Scholar 

  296. Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  297. 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).

    CAS  PubMed  Google Scholar 

  298. 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).

  299. Qin, S. et al. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol. 15, 1811–1822 (2019).

    CAS  PubMed  Google Scholar 

  300. 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).

    Google Scholar 

  301. 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).

  302. 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).

    PubMed  Google Scholar 

  303. 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).

    Google Scholar 

  304. 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).

    Google Scholar 

  305. 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).

    Google Scholar 

  306. Cichocki, F. et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Cancer Res. 77, 5664–5675 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  307. Takayama, T. et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356, 802–807 (2000).

    CAS  PubMed  Google Scholar 

  308. 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).

    PubMed  PubMed Central  Google Scholar 

  309. Di Blasi, D. et al. Unique T-cell populations define immune-inflamed hepatocellular carcinoma. Cell Mol. Gastroenterol. Hepatol. 9, 195–218 (2020).

    PubMed  Google Scholar 

  310. Zhang, Q. et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut 68, 2019–2031 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  311. 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).

    PubMed  PubMed Central  Google Scholar 

  312. 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).

    PubMed  PubMed Central  Google Scholar 

  313. 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).

    PubMed  PubMed Central  Google Scholar 

  314. 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).

    CAS  PubMed  Google Scholar 

Download references

Funding

T.F.G. was supported by the Intramural Research Program of the NIH, NCI (ZIA BC 011345).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tim F. Greten.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-00572-w

Keywords

This article is cited by

Search

Quick links