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  • Review Article
  • Published:

Advances in immunotherapy for hepatocellular carcinoma

Nature Reviews Gastroenterology & Hepatology volume 18, pages 525–543 (2021)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is a prevalent disease with a progression that is modulated by the immune system. Systemic therapy is used in the advanced stage and until 2017 consisted only of antiangiogenic tyrosine kinase inhibitors (TKIs). Immunotherapy with checkpoint inhibitors has shown strong anti-tumour activity in a subset of patients and the combination of the anti-PDL1 antibody atezolizumab and the VEGF-neutralizing antibody bevacizumab has or will soon become the standard of care as a first-line therapy for HCC, whereas the anti-PD1 agents nivolumab and pembrolizumab are used after TKIs in several regions. Other immune strategies such as adoptive T-cell transfer, vaccination or virotherapy have not yet demonstrated consistent clinical activity. Major unmet challenges in HCC checkpoint immunotherapy are the discovery and validation of predictive biomarkers, advancing treatment to earlier stages of the disease, applying the treatment to patients with liver dysfunction and the discovery of more effective combinatorial or sequential approaches. Combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC and some are already under evaluation in large-scale clinical trials. This Review provides up-to-date information on the best use of currently available immunotherapies in HCC and the therapeutic strategies under development.

Key points

  • Multiple immune mechanisms are important in the development and progression of hepatocellular carcinoma (HCC) and correlate with prognosis.

  • Checkpoint inhibitors targeting PD1 and PDL1 and CTLA4 are active, tolerable and clinically beneficial against advanced HCC.

  • At present, the best available first-line treatment for advanced HCC is a combination of PDL1 blockade with atezolizumab and VEGF blockade with bevacizumab.

  • There is as yet an almost complete lack of suitable biomarkers to guide the development of checkpoint inhibitors and their combinations in HCC.

  • Immunotherapy is likely to synergize with local and locoregional interventions in earlier stages of HCC.

  • Other promising forms of immunotherapy for HCC such as additional checkpoint inhibitors, adoptive cell transfer, vaccination and virotherapy are being actively pursued.

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Fig. 1: Key players in the hepatocellular carcinoma immune tumour microenvironment.
Fig. 2: Expanding the efficacy of ICIs in HCC through combination strategies.
Fig. 3: Combinations of ICIs with other systemic agents.
Fig. 4: Immunotherapy of HCC in 2021.

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References

  1. Ferlay, J. et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int. J. Cancer 144, 1941–1953 (2019).

    Article  CAS  PubMed  Google Scholar 

  2. WHO. Liver. http://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf (2018).

  3. Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2, 16018 (2016).

    Article  PubMed  Google Scholar 

  4. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J. Hepatol. 69, 182–236 (2018). A thorough and updated guidance on the management of HCC.

    Article  Google Scholar 

  5. Heimbach, J. K. et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67, 358–380 (2018).

    Article  PubMed  Google Scholar 

  6. Vogel, A. et al. Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 29, iv238–iv255 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Omata, M. et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol. Int. 11, 317–370 (2017).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Lencioni, R. et al. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: the SPACE trial. J. Hepatol. 64, 1090–1098 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Kudo, M. et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: a randomized phase III trial. Hepatology 60, 1697–1707 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Bruix, J. et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 16, 1344–1354 (2015).

    Article  CAS  PubMed  Google Scholar 

  12. 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).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhu, A. X. et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Oncol. 20, 282–296 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  17. Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cai, L. et al. Defective HLA class I antigen processing machinery in cancer. Cancer Immunol. Immunother. 67, 999–1009 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Velcheti, V. & Schalper, K. Basic overview of current immunotherapy approaches in cancer. Am. Soc. Clin. Oncol. Educ. Book 35, 298–308 (2016).

    Article  PubMed  Google Scholar 

  20. Chen, L. & Flies, D. B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 13, 227–242 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. He, X. & Xu, C. Immune checkpoint signaling and cancer immunotherapy. Cell Res. 30, 660–669 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Jain, N., Nguyen, H., Chambers, C. & Kang, J. Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc. Natl Acad. Sci. USA 107, 1524–1528 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Flecken, T. et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 59, 1415–1426 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Yarchoan, M., Johnson, B. A., Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Luksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Malekzadeh, P. et al. Antigen experienced T cells from peripheral blood recognize p53 neoantigens. Clin. Cancer Res. 26, 1267–1276 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Efremova, M., Finotello, F., Rieder, D. & Trajanoski, Z. Neoantigens generated by individual mutations and their role in cancer immunity and immunotherapy. Front. Immunol. 8, 1679 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  PubMed  Google Scholar 

  33. Fujimoto, A. et al. Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer. Nat. Genet. 48, 500–509 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Crispe, I. N. The liver as a lymphoid organ. Annu. Rev. Immunol. 27, 147–163 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Ebrahimkhani, M. R., Mohar, I. & Crispe, I. N. Cross-presentation of antigen by diverse subsets of murine liver cells. Hepatology 54, 1379–1387 (2011).

    Article  CAS  PubMed  Google Scholar 

  36. Krenkel, O. & Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 17, 306–321 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Ormandy, L. et al. Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res. 65, 2457–2464 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Shetty, S., Lalor, P. F. & Adams, D. H. Liver sinusoidal endothelial cells – gatekeepers of hepatic immunity. Nat. Rev. Gastroenterol. Hepatol. 15, 555–567 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Höchst, B. et al. Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J. Hepatol. 59, 528–535 (2013).

    Article  PubMed  CAS  Google Scholar 

  40. Dunham, R. M. et al. Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. J. Immunol. 190, 2009–2016 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yu, M. C. et al. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 40, 1312–1321 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Cariani, E. et al. HLA and killer immunoglobulin-like receptor genes as outcome predictors of hepatitis C virus-related hepatocellular carcinoma. Clin. Cancer Res. 19, 5465–5473 (2013).

    Article  CAS  PubMed  Google Scholar 

  43. Cariani, E. et al. Natural killer cells phenotypic characterization as an outcome predictor of HCV-linked HCC after curative treatments. Oncoimmunology 5, e1154249 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Zhang, Q. F. et al. Liver-infiltrating CD11b-CD27- NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression. Cell. Mol. Immunol. 14, 819–829 (2017).

    Article  CAS  PubMed  Google Scholar 

  46. Fu, J. et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132, 2328–2339 (2007).

    Article  PubMed  Google Scholar 

  47. Gao, Q. et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J. Clin. Oncol. 25, 2586–2593 (2007).

    Article  PubMed  Google Scholar 

  48. Chen, K. J. et al. Selective recruitment of regulatory T cell through CCR6-CCL20 in hepatocellular carcinoma fosters tumor progression and predicts poor prognosis. PLoS ONE 6, e24671 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    Article  CAS  PubMed  Google Scholar 

  50. Veglia, F., Perego, M. & Gabrilovich, D. Myeloid-derived suppressor cells coming of age. Nature Immunology 19, 108–119 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. Xiao, X. et al. PD-1hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov. 6, 546–559 (2016).

    Article  CAS  PubMed  Google Scholar 

  53. Zhao, F. et al. Human CCR4+ CCR6+ Th17 cells suppress autologous CD8+ T cell responses. J. Immunol. 188, 6055–6062 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Han, Y. et al. Human CD14+CTLA-4+ regulatory dendritic cells suppress T-cell response by cytotoxic T-lymphocyte antigen-4-dependent IL-10 and indoleamine-2,3-dioxygenase production in hepatocellular carcinoma. Hepatology 59, 567–579 (2014).

    Article  CAS  PubMed  Google Scholar 

  55. Affo, S., Yu, L.-X. & Schwabe, R. F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol. Mech. Dis. 12, 153–186 (2017).

    Article  CAS  Google Scholar 

  56. 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.e17 (2016).

    Article  CAS  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ji, J. et al. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 62, 481–495 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Luke, J. J., Bao, R., Sweis, R. F., Spranger, S. & Gajewski, T. F. WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin. Cancer Res. 25, 3074–3083 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Spranger, S. et al. Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma. Proc. Natl Acad. Sci. USA 113, E7759–E7768 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bray, S. M., Vujanovic, L. & Butterfield, L. H. Dendritic cell-based vaccines positively impact natural killer and regulatory T cells in hepatocellular carcinoma patients. Clin. Dev. Immunol. 2011, 249281 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Sánchez-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).

    Article  PubMed  CAS  Google Scholar 

  65. de Galarreta, M. R. et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 9, 1124–1141 (2019). A link between a frequent genetic alteration in HCC and resistance to ICIs in animal models.

    Article  Google Scholar 

  66. Harding, J. J. et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin. Cancer Res. 25, 2116–2126 (2019).

    Article  CAS  PubMed  Google Scholar 

  67. Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Fridman, W. H., Zitvogel, L., Sautès-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Peng, W. et al. Loss of PTEN promotes resistance to T cell–mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    Article  CAS  PubMed  Google Scholar 

  70. Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Duruisseaux, M. et al. Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis. Lancet Respir. Med. 6, 771–781 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Zhou, J. et al. Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int. J. Cancer 125, 1640–1648 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Horwitz, E. et al. Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to sorafenib treatment. Cancer Discov. 4, 730–743 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Glodde, N. et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity 47, 789–802.e9 (2017).

    Article  CAS  PubMed  Google Scholar 

  76. Sanmamed, M. F. et al. Serum interleukin-8 reflects tumor burden and treatment response across malignancies of multiple tissue origins. Clin. Cancer Res. 20, 5697–5707 (2014).

    Article  CAS  PubMed  Google Scholar 

  77. Tsai, J. H. F. et al. Elevated urinary transforming growth factor-β1 level as a tumour marker and predictor of poor survival in cirrhotic hepatocellular carcinoma. Br. J. Cancer 76, 244–250 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ritter, M. et al. Immunoregulation of dendritic and T cells by alpha-fetoprotein in patients with hepatocellular carcinoma. J. Hepatol. 41, 999–1007 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Pardee, A. D., Shi, J. & Butterfield, L. H. Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. J. Immunol. 193, 5723–5732 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Dong, L. Q. et al. Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma. J. Hepatol. 72, 896–908 (2020).

    Article  CAS  PubMed  Google Scholar 

  81. Kamimura, H. et al. Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence. J. Hepatol. 56, 381–388 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Makarova-Rusher, O. V., Medina-Echeverz, J., Duffy, A. G. & Greten, T. F. The yin and yang of evasion and immune activation in HCC. J. Hepatol. 62, 1420–1429 (2015).

    Article  CAS  PubMed  Google Scholar 

  83. Berraondo, P., Ochoa, M. C., Olivera, I. & Melero, I. Immune desertic landscapes in hepatocellular carcinoma shaped by β-catenin activation. Cancer Discov. 9, 1003–1005 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Montfort, A. et al. The TNF paradox in cancer progression and immunotherapy. Front. Immunol. 10, 1818 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhong, M. et al. Induction of tolerogenic dendritic cells by activated TGF-β/Akt/Smad2 signaling in RIG-I-deficient stemness-high human liver cancer cells. BMC Cancer 19, 439 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Zhang, F. et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget 7, 52294–52306 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Ahmadzadeh, M. & Rosenberg, S. A. TGF-β1 attenuates the acquisition and expression of effector function by tumor antigen-specific human memory CD8 T cells. J. Immunol. 174, 5215–5223 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Okumoto, K. et al. Possible contribution of circulating transforming growth factor-beta1 to immunity and prognosis in unresectable hepatocellular carcinoma. Liver Int. 24, 21–28 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Yamagiwa, S., Gray, J. D., Hashimoto, S. & Horwitz, D. A. A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J. Immunol. 166, 7282–7289 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Peng, L. et al. High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients. Oncotarget 8, 34387–34397 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Lin, T. H. et al. High serum transforming growth factor-β1 levels predict outcome in hepatocellular carcinoma patients treated with sorafenib. Clin. Cancer Res. 21, 3678–3684 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Feun, L. G. et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma. Cancer 125, 3603–3614 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Stewart, C. A. et al. Interferon-dependent IL-10 production by Tregs limits tumor Th17 inflammation. J. Clin. Invest. 123, 4859–4874 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yi, Y. et al. The functional impairment of HCC-infiltrating γδ T cells, partially mediated by regulatory T cells in a TGFβ- and IL-10-dependent manner. J. Hepatol. 58, 977–983 (2013).

    Article  CAS  PubMed  Google Scholar 

  96. Arihara, F. et al. Increase in CD14+HLA-DR-/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol. Immunother. 62, 1421–1430 (2013).

    Article  CAS  PubMed  Google Scholar 

  97. Shi, Y., Song, Q., Hu, D., Zhuang, X. & Yu, S. Tumor-infiltrating lymphocyte activity is enhanced in tumors with low IL-10 production in HBV-induced hepatocellular carcinoma. Biochem. Biophys. Res. Commun. 461, 109–114 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Courau, T. et al. TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies. JCI Insight 1, e85974 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Brown, Z. J. et al. Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma. Cancer Immunol. Immunother. 67, 1305–1315 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Cai, X. Y. et al. Overexpression of CD39 in hepatocellular carcinoma is an independent indicator of poor outcome after radical resection. Medicine 95, e4989 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Shali, S. et al. Ecto-5′-nucleotidase (CD73) is a potential target of hepatocellular carcinoma. J. Cell. Physiol. 234, 10248–10259 (2019).

    Article  CAS  PubMed  Google Scholar 

  103. Lee, I. C. et al. Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments. Int. J. Cancer 133, 2895–2902 (2013).

    Article  CAS  PubMed  Google Scholar 

  104. Nagao, M. et al. The impact of interferon gamma receptor expression on the mechanism of escape from host immune surveillance in hepatocellular carcinoma. Hepatology 32, 491–500 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Shi, F. et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int. J. Cancer 128, 887–896 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Zabala, M. et al. Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer. J. Hepatol. 47, 807–815 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. 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). The first clinical trial of immunotherapy in HCC, showing activity of CTLA4 blockade.

    Article  CAS  PubMed  Google Scholar 

  108. 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). The first clinical trial to show consistent antitumor activity of PD1 blockade in HCC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    Article  PubMed  Google Scholar 

  110. 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).

    Article  CAS  PubMed  Google Scholar 

  111. 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) [abstract LBA38_PR]. Ann. Oncol. 30 (Suppl. 5), v874–v875 (2019).

    Article  Google Scholar 

  112. Sangro, B. et al. CheckMate 459: long-term (minimum follow-up 33.6 months) survival outcomes with nivolumab versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma [abstract LBA-3]. Ann. Oncol. 31 (Suppl. 3), S241–S242 (2020).

    Article  Google Scholar 

  113. Gao, Q. et al. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin. Cancer Res. 15, 971–979 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Li, H. et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56, 1342–1351 (2012).

    Article  CAS  PubMed  Google Scholar 

  115. Yan, W. et al. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut 64, 1593–1604 (2015).

    Article  CAS  PubMed  Google Scholar 

  116. Du, W. et al. Tim-3 as a target for cancer immunotherapy and mechanisms of action. Int. J. Mol. Sci. 18, 645 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  117. Gautron, A. S., Dominguez-Villar, M., de Marcken, M. & Hafler, D. A. Enhanced suppressor function of TIM-3+FoxP3+ regulatory T cells. Eur. J. Immunol. 44, 2703–2711 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Li, Z. et al. Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma. Medicine 95, e5749 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Andrews, L. P., Marciscano, A. E., Drake, C. G. & Vignali, D. A. A. LAG3 (CD223) as a cancer immunotherapy target. Immunol. Rev. 276, 80–96 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhou, G. et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology 153, 1107–1119.e10 (2017).

    Article  CAS  PubMed  Google Scholar 

  121. Wang, J. et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176, 334–347.e12 (2019).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  123. Yau, T. et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040 [abstract]. J. Clin. Oncol. 37 (Suppl. 15), 4012 (2019).

    Article  Google Scholar 

  124. Kelley, R. K. et al. Efficacy, tolerability, and biologic activity of a novel regimen of tremelimumab (T) in combination with durvalumab (D) for patients (pts) with advanced hepatocellular carcinoma (aHCC) [abstract]. J. Clin. Oncol. 38 (Suppl. 15), 4508 (2020).

    Article  Google Scholar 

  125. Ascierto, P. A. et al. Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 18, 611–622 (2017).

    Article  CAS  PubMed  Google Scholar 

  126. Callahan, M. K. et al. Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab [abstract]. J. Clin. Oncol. 31 (Suppl. 15), 3003 (2013).

    Article  Google Scholar 

  127. Zhu, A. X. et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC) [abstract]. J. Clin. Oncol. 38 (Suppl. 15), 4519 (2020).

    Article  Google Scholar 

  128. Yau, T. et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040 [abstract]. J. Clin. Oncol. 38 (Suppl. 4), 478 (2020).

    Article  Google Scholar 

  129. Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020). The pivotal clinical trial that has established a combination of an anti-PD1 and an anti -VEGF as the standard of care for first-line systemic therapy in HCC.

    Article  CAS  PubMed  Google Scholar 

  130. Finn, R. S. et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC) [abstract]. J. Clin. Oncol. 39 (Suppl. 3), 267 (2021).

    Article  Google Scholar 

  131. Lee, M. et al. Randomised efficacy and safety results for atezolizumab (atezo) + bevacizumab (bev) in patients (pts) with previously untreated, unresectable hepatocellular carcinoma (HCC) [abstract LBA39]. Ann. Oncol. 30 (Suppl. 5), v875 (2019).

    Article  Google Scholar 

  132. Siegel, A. B. et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J. Clin. Oncol. 26, 2992–2998 (2008).

    Article  CAS  PubMed  Google Scholar 

  133. Boige, V. et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist 17, 1063–1072 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ren, Z. et al. Sintilimab plus bevacizumab biosimilar vs sorafenib as first-line treatment for advanced hepatocellular carcinoma (ORIENT-32)2 [abstract LBA2]. Ann. Oncol. 31 (Suppl. 6), S1287 (2020).

    Article  Google Scholar 

  135. Rahma, O. E. & Hodi, F. S. The intersection between tumor angiogenesis and immune suppression. Clin. Cancer Res. 25, 5449–5457 (2019).

    Article  CAS  PubMed  Google Scholar 

  136. Feng, P.-H. et al. Bevacizumab reduces S100A9-positive MDSCs linked to intracranial control in patients with EGFR-mutant lung adenocarcinoma. J. Thorac. Oncol. 13, 958–967 (2018).

    Article  PubMed  Google Scholar 

  137. Limagne, E. et al. Accumulation of MDSC and Th17 cells in patients with metastatic colorectal cancer predicts the efficacy of a FOLFOX-bevacizumab drug treatment regimen. Cancer Res. 76, 5241–5252 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Shigeta, K. et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology 71, 1247–1261 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Fabian, M. A. et al. A small molecule-kinase interaction map for clinical kinase inhibitors. Nat. Biotechnol. 23, 329–336 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    Article  CAS  PubMed  Google Scholar 

  141. Sangro, B. et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J. Hepatol. 72, 320–341 (2020). A thorough guidance on how to manage the toxicity of ICIs in HCC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Yau, T. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 6, e204564 (2020). The first clinical trial to show improved activity with the dual blockade of CTLA4 and PD1.

    Article  PubMed  PubMed Central  Google Scholar 

  143. Duan, J. et al. Use of immunotherapy with programmed cell death 1 vs programmed cell death ligand 1 inhibitors in patients with cancer: a systematic review and meta-analysis. JAMA Oncol. 6, 375–384 (2020).

    Article  PubMed  Google Scholar 

  144. Spain, L., Diem, S. & Larkin, J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat. Rev. 44, 51–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Vollmer, O. et al. Characterization of auto-immune hepatitis associated with the use of anti-TNFα agents: an analysis of 389 cases in VigiBase. Autoimmun. Rev. 19, 102460 (2020).

    Article  CAS  PubMed  Google Scholar 

  146. Peeraphatdit, T. B. et al. Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology 72, 315–329 (2020).

    Article  PubMed  Google Scholar 

  147. Geiger-Gritsch, S. et al. Safety of bevacizumab in patients with advanced cancer: a meta-analysis of randomized controlled trials. Oncologist 15, 1179–1191 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Brusilovskaya, K., Königshofer, P., Schwabl, P. & Reiberger, T. Vascular targets for the treatment of portal hypertension. Semin. Liver Dis. 39, 483–501 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Reiberger, T. et al. Sorafenib attenuates the portal hypertensive syndrome in partial portal vein ligated rats. J. Hepatol. 51, 865–873 (2009).

    Article  CAS  PubMed  Google Scholar 

  150. Scheiner, B. et al. Short- and long-term effects of transarterial chemoembolization on portal hypertension in patients with hepatocellular carcinoma. United Eur. Gastroenterol. J. 7, 850–858 (2019).

    Article  Google Scholar 

  151. Rimola, J. et al. Radiological response to nivolumab in patients with hepatocellular carcinoma: a multicenter analysis of real-life practice. Eur. J. Radiol. 135, 109484 (2021).

    Article  PubMed  Google Scholar 

  152. El-Khoueiry, A. B. et al. Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): subanalyses of CheckMate-040 [abstract]. J. Clin. Oncol. 36 (Suppl. 4), 475 (2018).

    Article  Google Scholar 

  153. Reig, M. et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J. Hepatol. 61, 318–324 (2014).

    Article  CAS  PubMed  Google Scholar 

  154. Wong, L. et al. Association between immune-related adverse events and efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma [abstract 325P]. Ann. Oncol. 30 (Suppl. 9), ix110 (2019).

    Article  Google Scholar 

  155. Gordan, J. D. et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J. Clin. Oncol. 38, 4317–4345 (2020).

    Article  CAS  PubMed  Google Scholar 

  156. Pelizzaro, F. et al. Capecitabine in advanced hepatocellular carcinoma: a multicenter experience. Dig. Liver Dis. 51, 1713–1719 (2019).

    Article  CAS  PubMed  Google Scholar 

  157. Sangro, B. et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J. Hepatol. 73, 1460–1469 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Calderaro, J. et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 64, 2038–2046 (2016). A comprehensive study of the clinical and pathological correlations of PDL1 expression in HCC.

    Article  CAS  PubMed  Google Scholar 

  159. Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Liu, X. S. & Mardis, E. R. Applications of immunogenomics to cancer. Cell 168, 600–612 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jiang, P. et al. Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response. Nat. Med. 24, 1550–1558 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Pillai, R. N. et al. Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: a systematic analysis of the literature. Cancer 124, 271–277 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. Latchman, Y. et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2, 261–268 (2001).

    Article  CAS  PubMed  Google Scholar 

  165. Sugiura, D. et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science 364, 558–566 (2019).

    Article  CAS  PubMed  Google Scholar 

  166. Davda, J. et al. Immunogenicity of immunomodulatory, antibody-based, oncology therapeutics. J. Immunother. Cancer 7, 105 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  167. van Brummelen, E. M. J., Ros, W., Wolbink, G., Beijnen, J. H. & Schellens, J. H. M. Antidrug antibody formation in oncology: clinical relevance and challenges. Oncologist 21, 1260–1268 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. FDA. Highlights of Prescribing Information: TECENTRIQ. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761034s025lbl.pdf (2020).

  169. Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Cappuzzello, E., Sommaggio, R., Zanovello, P. & Rosato, A. Cytokines for the induction of antitumor effectors: the paradigm of cytokine-induced killer (CIK) cells. Cytokine Growth Factor Rev. 36, 99–105 (2017).

    Article  CAS  PubMed  Google Scholar 

  172. Rosenberg, S. A. et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N. Engl. J. Med. 313, 1485–1492 (1985).

    Article  CAS  PubMed  Google Scholar 

  173. Rosenberg, S. A., Spiess, P. & Lafreniere, R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science 233, 1318–1321 (1986).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  175. Lu, P. H. & Negrin, R. S. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J. Immunol. 153, 1687–1696 (1994).

    CAS  PubMed  Google Scholar 

  176. Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391.e6 (2015).

    Article  CAS  PubMed  Google Scholar 

  177. Jiang, S. S. et al. A phase I clinical trial utilizing autologous tumor-infiltrating lymphocytes in patients with primary hepatocellular carcinoma. Oncotarget 6, 41339–41349 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Lee, H. J., Kim, S. K., Cho, D. & Lee, J. J. Cellular immunotherapy as a beacon of hope for hematological malignancies. Blood Res. 50, 126–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Gao, H. et al. Development of T cells redirected to glypican-3 for the treatment of hepatocellular carcinoma. Clin. Cancer Res. 20, 6418–6428 (2014).

    Article  CAS  PubMed  Google Scholar 

  180. Jiang, Z. et al. Anti-GPC3-CAR T cells suppress the growth of tumor cells in patient-derived xenografts of hepatocellular carcinoma. Front. Immunol. 7, 690 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. 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).

    Article  CAS  PubMed  Google Scholar 

  182. Sun, L. et al. Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma. Tumor Biol. 37, 799–806 (2016).

    Article  CAS  Google Scholar 

  183. Gerry, A. B. et al. Improved affinity AFP-specific T cell receptor for hepatocellular carcinoma. J. Immunother. Cancer 1, P10 (2013).

    Article  PubMed Central  Google Scholar 

  184. Malekzadeh, P. et al. Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers. J. Clin. Invest. 129, 1109–1114 (2019).

    Article  PubMed  Google Scholar 

  185. Hu, Z., Ott, P. A. & Wu, C. J. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18, 168–182 (2018). A review on the field of tumour neoantigen-based vaccines, discussing developments and future directions for this treatment strategy.

    Article  CAS  PubMed  Google Scholar 

  186. Tagliamonte, M. et al. Potentiating cancer vaccine efficacy in liver cancer. Oncoimmunology 7, e1488564 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Hammerich, L. et al. Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination. Nat. Med. 25, 814–824 (2019).

    Article  CAS  PubMed  Google Scholar 

  188. Coulie, P. G., Van Den Eynde, B. J., Van Der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).

    Article  CAS  PubMed  Google Scholar 

  189. 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).

    Article  CAS  PubMed  Google Scholar 

  190. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Rammensee, H.-G. & Singh-Jasuja, H. HLA ligandome tumor antigen discovery for personalized vaccine approach. Expert Rev. Vaccin. 12, 1211–1217 (2013).

    Article  CAS  Google Scholar 

  192. Buonaguro, L. & HEPAVAC Consortium. Developments in cancer vaccines for hepatocellular carcinoma. Cancer Immunol. Immunother. 65, 93–99 (2016).

    Article  CAS  PubMed  Google Scholar 

  193. Chen, F. et al. Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors. J. Clin. Invest. 129, 2056–2070 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).

    Article  CAS  PubMed  Google Scholar 

  196. Vercher, E. et al. Identification of neoantigen-reactive T cells in hepatocellular carcinoma: implication in adoptive T cell therapy. J. Hepatol. 73, S39–S40 (2020).

    Article  Google Scholar 

  197. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  PubMed  Google Scholar 

  198. Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    Article  CAS  PubMed  Google Scholar 

  199. Vanpouille-Box, C., Hoffmann, J. A. & Galluzzi, L. Pharmacological modulation of nucleic acid sensors – therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 18, 845–867 (2019).

    Article  CAS  PubMed  Google Scholar 

  200. Yang, D., Han, Z. & Oppenheim, J. J. Alarmins and immunity. Immunol. Rev. 280, 41–56 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Rodriguez-Ruiz, M. E., Vitale, I., Harrington, K. J., Melero, I. & Galluzzi, L. Immunological impact of cell death signaling driven by radiation on the tumor microenvironment. Nat. Immunol. 21, 120–134 (2020).

    Article  CAS  PubMed  Google Scholar 

  202. Smith, M. et al. Trial Watch: Toll-like receptor agonists in cancer immunotherapy. OncoImmunology 7, e1526250 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Flood, B. A., Higgs, E. F., Li, S., Luke, J. J. & Gajewski, T. F. STING pathway agonism as a cancer therapeutic. Immunol. Rev. 290, 24–38 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Márquez-Rodas, I. et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci. Transl. Med. 12, eabb0391 (2020).

    Article  PubMed  CAS  Google Scholar 

  205. Bhatia, S. et al. Intratumoral G100, a TLR4 agonist, induces antitumor immune responses and tumor regression in patients with Merkel cell carcinoma. Clin. Cancer Res. 25, 1185–1195 (2019).

    Article  CAS  PubMed  Google Scholar 

  206. Aznar, M. A. et al. Intratumoral delivery of immunotherapy–act locally, think globally. J. Immunol. 198, 31–39 (2017).

    Article  CAS  PubMed  Google Scholar 

  207. Tenneti, P., Borad, M. J. & Babiker, H. M. Exploring the role of oncolytic viruses in hepatobiliary cancers. Immunotherapy 10, 971–986 (2018).

    Article  CAS  PubMed  Google Scholar 

  208. Melero, I. et al. Repurposing infectious disease vaccines for intratumoral immunotherapy. J. Immunother. Cancer 8, e000443 (2020).

    Article  PubMed  Google Scholar 

  209. Rodríguez-Ruiz, M. E. et al. Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients. Ann. Oncol. 29, 1312–1319 (2018).

    Article  PubMed  Google Scholar 

  210. Mizukoshi, E. et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology 57, 1448–1457 (2013).

    Article  CAS  PubMed  Google Scholar 

  211. Sangro, B. et al. Nivolumab in sorafenib-naive and -experienced patients with advanced hepatocellular carcinoma (HCC): survival, hepatic safety, and biomarker assessments in CheckMate-040 [abstract 141]. Hepatology 66 (Suppl. 1), 82A (2017).

    Google Scholar 

  212. Qin, S. et al. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 21, 571–580 (2020).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

S.H.-S. receives funding from ISCIII/FEDER, UE (PI18/00556), and Gobierno de Navarra (Departamento de Salud (045-2017)) co-financed (50%) with FEDER funds (UE, FEDER 2014-2020 “Una manera de hacer Europa”). I.M. receives funding from MINECO SAF2014-52361-R and SAF 2017-83267-C2-1R; Worldwide Cancer Research Grant (15-1146); the Asociacion Española Contra el Cancer (AECC) Foundation under grant GCB15152947MELE; and the European Union’s Horizon 2020 Program (grant agreement no. 635122 PROCROP). B.S. receives funding from ISCIII/EU TRANSCAN-2 (AC16/00065) and ISCIII FIS (PI19/00742). P.S. receives funding from Instituto de Salud Carlos III co-financed by European FEDER funds (PI17/00249 and PI20/00260), Fundación Bancaria La Caixa “Hepacare” project, and “Murchante contra el Cáncer” initiative.

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Authors and Affiliations

  1. Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain

    Bruno Sangro

  2. Program of Immunology and Immunotherapy, CIMA de la Universidad de Navarra, IDISNA and CIBEREHD, Pamplona, Spain

    Pablo Sarobe, Sandra Hervás-Stubbs & Ignacio Melero

  3. Department of Immunology and Immunotherapy, Clinica Universidad de Navarra-IDISNA and CIBERONC, Pamplona, Spain

    Ignacio Melero

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Corresponding author

Correspondence to Bruno Sangro.

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Competing interests

I.M. reports advisory roles with Roche-Genentech, Bristol-Myers Squibb, CYTOMX, Incyte, MedImmune, Tusk, F-Star, Genmab, Molecular Partners, Alligator, Bioncotech, MSD, Merck Serono, Boehringer Ingelheim, Astra Zeneca, Numab, Catalym and Bayer, and research funding from Roche, BMS, Alligator and Bioncotech. B.S. reports consultancy fees from Adaptimmune, Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical and Terumo and speaker fees from Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo BMS and Sirtex Medical. P.S. and S.H.-S. report no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks A.-L. Cheng, P. Galle, A. Zhu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Biomarker

Biological parameter assessed in the laboratory that enables predicting or following the effects of a given treatment; identification of predictive biomarkers is important in selecting patients who would benefit from treatment.

Vascular endothelial growth factor

(VEGF). A family of soluble proteins that regulate angiogenesis of blood and lymphatic vessels acting on receptors encompassing intracellular tyrosine kinase domains; VEGFA is considered the main pro-angiogenic factor in human malignancies including HCC.

Tumour microenvironment

Cellular and molecular components of the malignant tissue in which tumour and stromal cells exist in a mutual relationship in which each cell type shapes the functions of the other.

Myeloid-derived suppressor cells

Immature haematopoietic cells of myeloid lineage resembling either macrophages or neutrophils that are abundant in patients with advanced cancer and are able to inhibit T cell responses.

Immune checkpoint

Surface receptor expressed on immune system cells that downregulates the intensity of immune responses or prevents their onset; neutralization with monoclonal antibodies of checkpoint receptors or their ligands known as checkpoint inhibitors restores immune responses to cancer.

Cytotoxic T lymphocyte-associated antigen 4

(CTLA4). Co-inhibitory surface glycoprotein also known as CD152 that is expressed on activated T cells and constitutively on regulatory T cells and that shows homology and shares ligands with CD28; it is known as an immune checkpoint inhibitor that upon ligation downregulates T cell-mediated immune responses to avoid autoimmunity.

PD1

Checkpoint inhibitor molecule also known as CD279 expressed on the membrane of activated and exhausted T cells that, upon ligation by its cognate ligand PDL1, downregulates immune responses bringing tyrosine phosphatases, mainly SHP-2, to activating immune synapses.

Therapeutic cancer vaccines

Formulation of cancer-expressed antigens in an immunogenic fashion, given to patients to elicit specific immune responses against malignant cells; adjuvant components enhance immunogenicity by promoting focal inflammation at the site of administration.

Cancer neoantigens

Exclusive protein sequence expressed by cancer cells as a result of a non-synonymous mutation that is presented by self-MHC antigen-presenting molecules and is able to elicit cancer-specific immune responses.

T cell receptor

(TCR). A clonally distributed antigen-specific receptor expressed on the surface of T cells that specifically recognizes peptides presented by MHC antigen-presenting molecules and initiates intracellular signalling via the CD3 complex.

Tumour mutational burden

(TMB). Number of mutations per megabase of exonic DNA in tumour cells as compared with non-transformed cells of the same individual; it is usually expressed as number of mutations per megabase and correlates with the probability of T cell recognizable neoantigens in a given tumour.

Ectonucleotidases CD39 and CD73

Surface enzymes expressed by tumour and non-tumour cells in the tumour microenvironment that synthesize the immunosuppressive metabolite adenosine from ATP.

Immune-mediated adverse events

(IMAEs). Series of adverse effects following treatment with checkpoint inhibitors that resemble organ-specific autoimmune conditions.

Chimeric antigen receptors

(CARs). Fusion proteins composed of a single-chain antibody that recognizes a surface tumour protein linked to a transmembrane domain; these constructs are usually transfected to T cells with retroviral vectors to artificially confer the ability to recognize and destroy cancer cells.

Immunogenic cell death

A form of cell death that provokes immunity against the cell’s antigenic components and that usually accompanies stressful or non-programmed cell death; it is mediated by alarmins that are recognized by innate receptors on immune cells, especially dendritic cells.

Toll-like receptor

A member of the family of surface and endosomal proteins that have evolved to detect pathogen-associated molecular patterns that denote the presence of moieties exclusively present in prokaryotic cells.

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Sangro, B., Sarobe, P., Hervás-Stubbs, S. et al. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 18, 525–543 (2021). https://doi.org/10.1038/s41575-021-00438-0

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