Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells.
HCC
immunotherapy
innate immunity
tumor microenvironment
Journal
Cellular & molecular immunology
ISSN: 2042-0226
Titre abrégé: Cell Mol Immunol
Pays: China
ID NLM: 101242872
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
10
09
2020
accepted:
29
09
2020
pubmed:
26
11
2020
medline:
28
12
2021
entrez:
25
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33235387
doi: 10.1038/s41423-020-00572-w
pii: 10.1038/s41423-020-00572-w
pmc: PMC7852696
doi:
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
112-127Références
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: 30207593
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
pubmed: 31912902
Pawlotsky, J. M. Pathophysiology of hepatitis C virus infection and related liver disease. Trends Microbiol. 12, 96–102 (2004).
pubmed: 15036326
Trepo, C., Chan, H. L. & Lok, A. Hepatitis B virus infection. Lancet 384, 2053–2063 (2014).
pubmed: 24954675
Morgan, T. R., Mandayam, S. & Jamal, M. M. Alcohol and hepatocellular carcinoma. Gastroenterology 127, S87–S96 (2004).
pubmed: 15508108
Gao, B. & Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141, 1572–1585 (2011).
pubmed: 21920463
pmcid: 3214974
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: 31028350
Zhang, D. Y. & Friedman, S. L. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 56, 769–775 (2012).
pubmed: 22378017
pmcid: 4087159
Clavien, P. A. et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol. 13, e11–e22 (2012).
pubmed: 22047762
Vitale, A. et al. Personalized treatment of patients with very early hepatocellular carcinoma. J. Hepatol. 66, 412–423 (2017).
pubmed: 27677712
Forner, A., Reig, M. & Bruix, J. Hepatocellular carcinoma. Lancet 391, 1301–1314 (2018).
pubmed: 29307467
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).
pubmed: 27084738
pmcid: 4943317
Hoos, A. Development of immuno-oncology drugs—from CTLA4 to PD1 to the next generations. Nat. Rev. Drug Discov. 15, 235–247 (2016).
pubmed: 26965203
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).
pubmed: 31954494
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).
pubmed: 32587357
pmcid: 7316832
Cao, D. et al. Identification of immunological subtypes of hepatocellular carcinoma with expression profiling of immune-modulating genes. Aging 12, 12187–12205 (2020).
pubmed: 32544882
pmcid: 7343492
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).
pubmed: 29603348
Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830 e814 (2018).
pubmed: 29628290
pmcid: 5982584
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).
pubmed: 32509418
pmcid: 7249423
Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949.e16 (2017).
pubmed: 29033130
pmcid: 5685550
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
pubmed: 25428505
pmcid: 4246418
Havel, J. J., Chowell, D. & Chan, T. A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer 19, 133–150 (2019).
pubmed: 30755690
pmcid: 6705396
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).
pubmed: 28741618
Heymann, F. & Tacke, F. Immunology in the liver-from homeostasis to disease. Nat. Rev. Gastroenterol. Hepatol. 13, 88–110 (2016).
pubmed: 26758786
Llovet, J. M. et al. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med. 359, 378–390 (2008).
pubmed: 18650514
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).
pubmed: 29433850
Callahan, M. K., Postow, M. A., Wolchok, J. D. & Targeting, T. Cell co-receptors for cancer therapy. Immunity 44, 1069–1078 (2016).
pubmed: 27192570
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).
pubmed: 28434648
pmcid: 7539326
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: 29875066
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).
pubmed: 23466307
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).
pubmed: 31790344
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
pubmed: 32402160
Chiang, D. Y. et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 68, 6779–6788 (2008).
pubmed: 18701503
pmcid: 2587454
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: 28465473
pmcid: 5503630
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).
pubmed: 31562797
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).
pubmed: 28678668
pmcid: 7587408
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).
pubmed: 29658845
pmcid: 7193684
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).
pubmed: 27816492
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).
pubmed: 29567707
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).
pubmed: 26250457
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).
pubmed: 24337625
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).
pubmed: 30232520
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).
pubmed: 22971679
pmcid: 3583872
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).
pubmed: 12649744
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).
pubmed: 22886490
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).
pubmed: 28188748
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).
pubmed: 22577059
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).
pubmed: 25354479
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: 20478057
pmcid: 2882353
Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. Med. 19, 329–336 (2013).
pubmed: 23396206
pmcid: 4268543
de Gramont, A., Faivre, S. & Raymond, E. Novel TGF-beta inhibitors ready for prime time in onco-immunology. Oncoimmunology 6, e1257453 (2017).
pubmed: 28197376
Bottcher, J. P., Knolle, P. A. & Stabenow, D. Mechanisms balancing tolerance and immunity in the liver. Dig. Dis. 29, 384–390 (2011).
pubmed: 21894009
Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013).
pubmed: 24202395
pmcid: 3954707
Binnewies, M. et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat. Med. 24, 541–550 (2018).
pubmed: 29686425
pmcid: 5998822
Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).
pubmed: 25592534
Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).
pubmed: 30142344
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).
pubmed: 32690952
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).
pubmed: 15489187
Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).
pubmed: 21212348
pmcid: 3089969
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).
pubmed: 12480696
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).
pubmed: 15536127
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).
pubmed: 9647249
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).
pubmed: 8768796
Tian, Z., Chen, Y. & Gao, B. Natural killer cells in liver disease. Hepatology 57, 1654–1662 (2013).
pubmed: 23111952
pmcid: 3573257
Collins, P. L. et al. Gene regulatory programs conferring phenotypic identities to human NK cells. Cell 176, 348–360.e312 (2019).
pubmed: 30595449
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).
pubmed: 30413361
pmcid: 6269138
Marquardt, N. et al. Cutting edge: identification and characterization of human intrahepatic CD49a+ NK cells. J. Immunol. 194, 2467–2471 (2015).
pubmed: 25672754
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).
pubmed: 26330348
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).
pubmed: 27210614
pmcid: 4876507
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).
pubmed: 30209347
Trinchieri, G. Biology of natural killer cells. Adv. Immunol. 47, 187–376 (1989).
pubmed: 2683611
pmcid: 7131425
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).
pubmed: 11282985
Lopez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).
pubmed: 28810142
Ringelhan, M., Pfister, D., O’Connor, T., Pikarsky, E. & Heikenwalder, M. The immunology of hepatocellular carcinoma. Nat. Immunol. 19, 222–232 (2018).
pubmed: 29379119
Lanier, L. L. Up on the tightrope: natural killer cell activation and inhibition. Nat. Immunol. 9, 495–502 (2008).
pubmed: 18425106
pmcid: 2669298
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).
pubmed: 23516982
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: 22449797
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).
pubmed: 16472598
Ljunggren, H. G. & Karre, K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol. Today 11, 237–244 (1990).
pubmed: 2201309
Karre, K. Natural killer cell recognition of missing self. Nat. Immunol. 9, 477–480 (2008).
pubmed: 18425103
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).
pubmed: 18824414
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).
pubmed: 21930732
Tu, Z. et al. TLR-dependent cross talk between human Kupffer cells and NK cells. J. Exp. Med. 205, 233–244 (2008).
pubmed: 18195076
pmcid: 2234385
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).
pubmed: 19551844
pmcid: 6357774
Li, T. et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 318, 154–161 (2012).
pubmed: 22182446
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).
pubmed: 29769244
pmcid: 6030494
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).
pubmed: 26847056
pmcid: 4947440
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).
pubmed: 28882429
pmcid: 5632228
Gauthier, L. et al. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Cell 177, 1701–1713.e1716 (2019).
pubmed: 31155232
Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391 e1386 (2015).
pubmed: 25747273
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: 28572802
pmcid: 5435757
Klose, C. S. & Artis, D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat. Immunol. 17, 765–774 (2016).
pubmed: 27328006
Wang, S. et al. Regulatory innate lymphoid cells control innate intestinal inflammation. Cell 171, 201–216.e218 (2017).
pubmed: 28844693
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).
pubmed: 28759001
Hazenberg, M. D. & Spits, H. Human innate lymphoid cells. Blood 124, 700–709 (2014).
pubmed: 24778151
Wagner, M. & Koyasu, S. Cancer Immunoediting by Innate Lymphoid Cells. Trends Immunol. 40, 415–430 (2019).
pubmed: 30992189
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: 32273975
pmcid: 7137177
Pedroza-Gonzalez, A. et al. Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. Oncoimmunology 4, e1008355 (2015).
pubmed: 26155417
pmcid: 4485712
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: 30979591
Wagner, M., Moro, K. & Koyasu, S. Plastic heterogeneity of innate lymphoid cells in cancer. Trends Cancer 3, 326–335 (2017).
pubmed: 28718410
Bal, S. M., Golebski, K. & Spits, H. Plasticity of innate lymphoid cell subsets. Nat. Rev. Immunol. 20, 552–565 (2020).
pubmed: 32107466
Colonna, M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48, 1104–1117 (2018).
pubmed: 29924976
pmcid: 6344351
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: 31586075
pmcid: 6778123
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).
pubmed: 31810881
Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).
pubmed: 26502405
pmcid: 4653079
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).
pubmed: 28613415
Neumann, K. et al. A proinflammatory role of type 2 innate lymphoid cells in murine immune-mediated hepatitis. J. Immunol. 198, 128–137 (2017).
pubmed: 27872212
Steinmann, S. et al. Hepatic ILC2 activity is regulated by liver inflammation-induced cytokines and effector CD4(+) T cells. Sci. Rep. 10, 1071 (2020).
pubmed: 31974518
pmcid: 6978388
Salimi, M. et al. Activated innate lymphoid cell populations accumulate in human tumour tissues. BMC Cancer 18, 341 (2018).
pubmed: 29587679
pmcid: 5870240
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).
pubmed: 24105680
Moral, J. A. et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature 579, 130–135 (2020).
pubmed: 32076273
pmcid: 7060130
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).
pubmed: 11592984
Bendelac, A. et al. CD1 recognition by mouse NK1+ T lymphocytes. Science 268, 863–865 (1995).
pubmed: 7538697
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).
pubmed: 7520467
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).
pubmed: 27457886
pmcid: 5745583
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).
pubmed: 23334244
Bellone, M. et al. iNKT cells control mouse spontaneous carcinoma independently of tumor-specific cytotoxic T cells. PLoS ONE 5, e8646 (2010).
pubmed: 20072624
pmcid: 2800182
Cui, J. et al. Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science 278, 1623–1626 (1997).
pubmed: 9374462
Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).
pubmed: 15032598
Kronenberg, M. Toward an understanding of NKT cell biology: progress and paradoxes. Annu. Rev. Immunol. 23, 877–900 (2005).
pubmed: 15771592
Lee, Y. J. et al. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity 43, 566–578 (2015).
pubmed: 26362265
pmcid: 4575275
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).
pubmed: 11466360
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).
pubmed: 15644449
Schrumpf, E. et al. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology 62, 1249–1259 (2015).
pubmed: 25855031
pmcid: 4589438
Syn, W. K. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323–1329 (2012).
pubmed: 22427237
pmcid: 3578424
Swann, J. B. et al. Type I natural killer T cells suppress tumors caused by p53 loss in mice. Blood 113, 6382–6385 (2009).
pubmed: 19234138
pmcid: 2710930
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).
pubmed: 19342695
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).
pubmed: 25314080
Syn, W. K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).
pubmed: 20512988
pmcid: 2920131
Wehr, A. et al. Chemokine receptor CXCR6-dependent hepatic NK T cell accumulation promotes inflammation and liver fibrosis. J. Immunol. 190, 5226–5236 (2013).
pubmed: 23596313
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: 30710528
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).
pubmed: 9576945
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).
pubmed: 17593666
Parekh, V. V. et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J. Clin. Investig. 115, 2572–2583 (2005).
pubmed: 16138194
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).
pubmed: 18451996
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).
pubmed: 21185787
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).
pubmed: 19302288
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).
pubmed: 17690880
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).
pubmed: 28651074
pmcid: 5604792
Treiner, E. et al. Selection of evolutionarily conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).
pubmed: 12634786
Le Bourhis, L. et al. Antimicrobial activity of mucosal-associated invariant T cells. Nat. Immunol. 11, 701–708 (2010).
pubmed: 20581831
Kjer-Nielsen, L. et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature 491, 717–723 (2012).
pubmed: 23051753
Corbett, A. J. et al. T-cell activation by transitory neo-antigens derived from distinct microbial pathways. Nature 509, 361–365 (2014).
pubmed: 24695216
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).
pubmed: 24101382
pmcid: 3804952
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).
pubmed: 10377186
pmcid: 2192962
Gherardin, N. A. et al. Human blood MAIT cell subsets defined using MR1 tetramers. Immunol. Cell Biol. 96, 507–525 (2018).
pubmed: 29437263
pmcid: 6446826
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).
pubmed: 25269706
Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).
pubmed: 21084709
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: 30723143
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: 26297765
Melo, A. M. et al. Mucosal-associated invariant T cells display diminished effector capacity in oesophageal adenocarcinoma. Front. Immunol. 10, 1580 (2019).
pubmed: 31354725
pmcid: 6635552
Ling, L. et al. Circulating and tumor-infiltrating mucosal associated invariant T (MAIT) cells in colorectal cancer patients. Sci. Rep. 6, 20358 (2016).
pubmed: 26837580
pmcid: 4738248
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).
pubmed: 28622514
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).
pubmed: 26497850
Kelly, J. et al. Chronically stimulated human MAIT cells are unexpectedly potent IL-13 producers. Immunol. Cell Biol. 97, 689–699 (2019).
pubmed: 31323167
pmcid: 6790710
Yan, J. et al. MAIT cells promote tumor initiation, growth, and metastases via tumor MR1. Cancer Discov. 10, 124–141 (2020).
pubmed: 31826876
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).
pubmed: 100039
Parker, C. M. et al. Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire. J. Exp. Med. 171, 1597–1612 (1990).
pubmed: 2185330
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: 25001861
Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of gammadelta T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).
pubmed: 23348415
pmcid: 3951794
Deseke, M. & Prinz, I. Ligand recognition by the gammadelta TCR and discrimination between homeostasis and stress conditions. Cell Mol. Immunol. 17, 914–924 (2020).
pubmed: 32709926
pmcid: 7608190
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).
pubmed: 32699351
pmcid: 7609273
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).
pubmed: 11748927
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).
pubmed: 20483730
pmcid: 2965829
Caccamo, N. et al. Differentiation, phenotype, and function of interleukin-17-producing human Vgamma9Vdelta2 T cells. Blood 118, 129–138 (2011).
pubmed: 21505189
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).
pubmed: 27791087
Itohara, S. et al. Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343, 754–757 (1990).
pubmed: 2154700
Goodman, T. & Lefrancois, L. Expression of the gamma-delta T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333, 855–858 (1988).
pubmed: 2968521
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).
pubmed: 32523311
pmcid: 7265152
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).
pubmed: 29758330
pmcid: 6089840
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: 25206355
pmcid: 4143964
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: 28067223
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).
pubmed: 1385768
pmcid: 1554410
Wang, X. & Tian, Z. gammadelta T cells in liver diseases. Front. Med. 12, 262–268 (2018).
pubmed: 29441440
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).
pubmed: 10359807
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: 23518691
pmcid: 3603285
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: 23483102
pmcid: 3583939
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).
pubmed: 17635809
Kunzmann, V. & Wilhelm, M. Anti-lymphoma effect of gammadelta T cells. Leuk. Lymphoma 46, 671–680 (2005).
pubmed: 16019504
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: 30894378
Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).
pubmed: 26193342
pmcid: 4852857
Cordova, A. et al. Characterization of human gammadelta T lymphocytes infiltrating primary malignant melanomas. PLoS ONE 7, e49878 (2012).
pubmed: 23189169
pmcid: 3506540
Meraviglia, S. et al. Distinctive features of tumor-infiltrating gammadelta T lymphocytes in human colorectal cancer. Oncoimmunology 6, e1347742 (2017).
pubmed: 29123962
pmcid: 5665062
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: 24568494
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).
pubmed: 23262246
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).
pubmed: 25660949
Silva-Santos, B., Serre, K. & Norell, H. Gammadelta T cells in cancer. Nat. Rev. Immunol. 15, 683–691 (2015).
pubmed: 26449179
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).
pubmed: 20549671
Jin, C. et al. Commensal microbiota promote lung cancer development via gammadelta T cells. Cell 176, 998–1013.e1016 (2019).
pubmed: 30712876
pmcid: 6691977
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).
pubmed: 25015833
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).
pubmed: 24816404
pmcid: 4716654
Ma, S. et al. IL-17A produced by gammadelta T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res. 74, 1969–1982 (2014).
pubmed: 24525743
Wilhelm, M. et al. Gammadelta T cells for immune therapy of patients with lymphoid malignancies. Blood 102, 200–206 (2003).
pubmed: 12623838
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).
pubmed: 16850345
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).
pubmed: 21847128
pmcid: 3171009
Hoeres, T., Smetak, M., Pretscher, D. & Wilhelm, M. Improving the efficiency of Vγ9Vδ2 T-cell immunotherapy in cancer. Front. Immunol. 9, 800 (2018).
pubmed: 29725332
pmcid: 5916964
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).
pubmed: 31492944
Zhao, Y., Niu, C. & Cui, J. Gamma-delta (gammadelta) T cells: friend or foe in cancer development? J. Transl. Med. 16, 3 (2018).
pubmed: 29316940
pmcid: 5761189
Rozenbaum, M. et al. Gamma-delta CAR-T cells show CAR-directed and independent activity against leukemia. Front. Immunol. 11, 1347 (2020).
pubmed: 32714329
pmcid: 7343910
Gomez Perdiguero, E. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015).
pubmed: 25470051
Tacke, F. & Zimmermann, H. W. Macrophage heterogeneity in liver injury and fibrosis. J. Hepatol. 60, 1090–1096 (2014).
pubmed: 24412603
Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).
pubmed: 26813785
pmcid: 4737801
Kiziltas, S. Toll-like receptors in pathophysiology of liver diseases. World J. Hepatol. 8, 1354–1369 (2016).
pubmed: 27917262
pmcid: 5114472
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).
pubmed: 13664867
pmcid: 2136961
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).
pubmed: 2642878
Gregory, S. H. & Wing, E. J. Neutrophil–Kupffer-cell interaction in host defenses to systemic infections. Immunol. Today 19, 507–510 (1998).
pubmed: 9818544
Li, P., He, K., Li, J., Liu, Z. & Gong, J. The role of Kupffer cells in hepatic diseases. Mol. Immunol. 85, 222–229 (2017).
pubmed: 28314211
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).
pubmed: 11160328
Kopydlowski, K. M. et al. Regulation of macrophage chemokine expression by lipopolysaccharide in vitro and in vivo. J. Immunol. 163, 1537–1544 (1999).
pubmed: 10415057
Knolle, P. et al. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. J. Hepatol. 22, 226–229 (1995).
pubmed: 7790711
Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).
pubmed: 19554540
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).
pubmed: 27302828
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).
pubmed: 25800956
pmcid: 4387291
Mencin, A., Kluwe, J. & Schwabe, R. F. Toll-like receptors as targets in chronic liver diseases. Gut 58, 704–720 (2009).
pubmed: 19359436
pmcid: 2791673
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).
pubmed: 25810240
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).
pubmed: 15989949
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).
pubmed: 26799785
pmcid: 4840057
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).
pubmed: 30936549
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).
pubmed: 18992916
Yeung, O. W. et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J. Hepatol. 62, 607–616 (2015).
pubmed: 25450711
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).
pubmed: 25181692
pmcid: 4253315
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).
pubmed: 26452628
Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).
pubmed: 27728804
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).
pubmed: 19826049
pmcid: 4397483
Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Investig. 125, 3356–3364 (2015).
pubmed: 26168215
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).
pubmed: 18485901
Wan, S., Kuo, N., Kryczek, I., Zou, W. & Welling, T. H. Myeloid cells in hepatocellular carcinoma. Hepatology 62, 1304–1312 (2015).
pubmed: 25914264
pmcid: 4589430
Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
pubmed: 22080947
Zhang, Q. et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell 179, 829–845.e820 (2019).
pubmed: 31675496
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: 28754304
pmcid: 5552238
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).
pubmed: 30414862
Forbes, S. J., Gupta, S. & Dhawan, A. Cell therapy for liver disease: from liver transplantation to cell factory. J. Hepatol. 62, S157–S169 (2015).
pubmed: 25920085
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).
pubmed: 21433043
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).
pubmed: 31604531
pmcid: 7233310
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: 29720116
pmcid: 5932869
Nakayama, M. Antigen presentation by MHC-dressed cells. Front. Immunol. 5, 672 (2014).
pubmed: 25601867
Thomson, A. W. & Knolle, P. A. Antigen-presenting cell function in the tolerogenic liver environment. Nat. Rev. Immunol. 10, 753–766 (2010).
pubmed: 20972472
Matta, B. M., Castellaneta, A. & Thomson, A. W. Tolerogenic plasmacytoid DC. Eur. J. Immunol. 40, 2667–2676 (2010).
pubmed: 20821731
pmcid: 3974856
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).
pubmed: 25446897
pmcid: 4254577
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).
pubmed: 27096321
pmcid: 4980762
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).
pubmed: 26493961
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).
pubmed: 28486109
pmcid: 5650691
Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018).
pubmed: 29942093
pmcid: 6475503
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).
pubmed: 29429633
pmcid: 5847168
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).
pubmed: 26900950
pmcid: 5154347
Ormandy, L. A. et al. Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J. Gastroenterol. 12, 3275–3282 (2006).
pubmed: 16718852
pmcid: 4087975
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).
pubmed: 16675576
Lee, J. H. et al. Adjuvant immunotherapy with autologous dendritic cells for hepatocellular carcinoma, randomized phase II study. Oncoimmunology 6, e1328335 (2017).
pubmed: 28811965
pmcid: 5543846
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: 18980227
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).
pubmed: 23516985
Saxena, M. & Bhardwaj, N. Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines. Curr. Opin. Immunol. 47, 35–43 (2017).
pubmed: 28732279
pmcid: 5626599
Chi, H. et al. Anti-tumor activity of Toll-like receptor 7 agonists. Front. Pharmacol. 8, 304 (2017).
pubmed: 28620298
pmcid: 5450331
Kyi, C. et al. Therapeutic immune modulation against solid cancers with intratumoral poly-ICLC: a pilot trial. Clin. Cancer Res. 24, 4937–4948 (2018).
pubmed: 29950349
pmcid: 6191332
Sahin, U. & Tureci, O. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).
pubmed: 29567706
Nemeth, T., Sperandio, M. & Mocsai, A. Neutrophils as emerging therapeutic targets. Nat. Rev. Drug Discov. 19, 253–275 (2020).
pubmed: 31969717
Shaul, M. E. & Fridlender, Z. G. Tumour-associated neutrophils in patients with cancer. Nat. Rev. Clin. Oncol. 16, 601–620 (2019).
pubmed: 31160735
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).
pubmed: 569013
Gerrard, T. L., Cohen, D. J. & Kaplan, A. M. Human neutrophil-mediated cytotoxicity to tumor cells. J. Natl Cancer Inst. 66, 483–488 (1981).
pubmed: 6937705
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).
pubmed: 6872356
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).
pubmed: 26924089
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).
pubmed: 28274999
pmcid: 5739867
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: 29556041
pmcid: 5859264
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).
pubmed: 22710437
Zhou, S. L. et al. Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56, 2242–2254 (2012).
pubmed: 22711685
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: 26918355
pmcid: 5239451
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).
pubmed: 25319848
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).
pubmed: 32328178
pmcid: 7171508
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: 24906014
pmcid: 4048155
Li, Y. W. et al. Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J. Hepatol. 54, 497–505 (2011).
pubmed: 21112656
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).
pubmed: 32024970
pmcid: 7115982
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: 30523282
Prieto, J., Melero, I. & Sangro, B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 12, 681–700 (2015).
pubmed: 26484443
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).
pubmed: 2839280
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).
pubmed: 27932229
Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).
pubmed: 29972759
pmcid: 7523244
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).
pubmed: 30665869
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).
pubmed: 30969136
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).
pubmed: 32716739
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).
pubmed: 28790065
pmcid: 5645243
Takayama, T. et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet 356, 802–807 (2000).
pubmed: 11022927
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: 30719425
pmcid: 6348253
Di Blasi, D. et al. Unique T-cell populations define immune-inflamed hepatocellular carcinoma. Cell Mol. Gastroenterol. Hepatol. 9, 195–218 (2020).
pubmed: 31445190
Zhang, Q. et al. Integrated multiomic analysis reveals comprehensive tumour heterogeneity and novel immunophenotypic classification in hepatocellular carcinomas. Gut 68, 2019–2031 (2019).
pubmed: 31227589
pmcid: 6839802
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: 27853178
pmcid: 5118541
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: 28412745
pmcid: 5421855
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: 28122337
pmcid: 5362414
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).
pubmed: 21145847