Immune microenvironment in hepatocellular carcinoma: current concepts and the role of blockade of immune checkpoints

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. The specificity of the immune microenvironment of an organ limits the possibilities of traditional therapeutic and surgical approaches to treatment, therefore one of the most important tasks of modern medicine is the search for new therapeutic targets targeting the tumor microenvironment. The introduction of checkpoint inhibitors into clinical practice expands immunotherapeutic options in the fight against liver cancer.

The purpose of our review is to summarize the available data on the liver immune microenvironment in hepatocellular carcinoma and to present advances in cancer immunotherapy using immune checkpoint blockade.

Material and methods. An analysis of the main foreign and domestic sources was carried out using the PubMed/Medline, ClinicalTrials.gov databases over the past 5 years.

Results. In terms of morbidity and mortality, hepatocellular carcinoma is included in the list of the most common malignant neoplasms in the world and the forecasts for the coming decades are disappointing. Modern approaches to immunotherapy, taking into account the tumor microenvironment, are associated with better survival rates and safety profiles than standard therapy.

Conclusion. The effectiveness of checkpoint inhibitors as monotherapy and combination strategies offers hope for improving the prognosis and quality of life of patients with unresectable HCC.

Full Text

Restricted Access

About the authors

Elena L. Bueverova

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: bueverova_e_l@staff.sechenov.ru
ORCID iD: 0000-0002-0700-9775

Cand. Sci. (Med.), Assoc. prof., Department of Internal Disease Propaedeutics, Gastroenterology and Hepatology

Russian Federation, Moscow

Oksana Yu. Zolnikova

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: zolnikova_o_yu@staff.sechenov.ru
ORCID iD: 0000-0002-6701-789X

Dr. Sci. (Med.), Professor, Department of Propaedeutics of Internal Diseases, Gastroenterology and Hepatology

Russian Federation, Moscow

Mikhail A. Paltsev

Lomonosov Moscow State University

Email: mpaltzev@gmail.com
ORCID iD: 0000-0002-5737-5706

Director, Center for Immunology and Molecular Biomedicine. Faculty of Biology

Russian Federation, Moscow

References

  1. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021; 71 (3): 209–49. doi: 10.3322/caac.21660.
  2. Rumgay H., Arnold M., Ferlay J., Lesi O., Cabasag C.J., Vignat J., Laversanne M., McGlynn K.A., Soerjomataram I. Global burden of primary liver cancer in 2020 and predictions to 2040. J. Hepatol. 2022; 77 (6): 1598–606. doi: 10.1016/j.jhep.2022.08.021.
  3. Xing R., Gao J., Cui Q., Wang Q. Strategies to Improve the Antitumor Effect of Immunotherapy for Hepatocellular Carcinoma. Front Immunol. 2021; 12: 783236. doi: 10.3389/fimmu.2021.783236.
  4. Llovet J.M., Kelley R.K., Villanueva A., Singal A.G., Pikarsky E., Roayaie S., Lencioni R., Koike K., Zucman-Rossi J., Finn R.S. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7 (1): 6. doi: 10.1038/s41572-020-00240-3.
  5. Michael L. Cheng, Diana Nakib, Catia T. Perciani, Sonya A. MacParland; The immune niche of the liver. Clin Sci (Lond) 29 October. 2021; 135 (20): 2445–66. DOI: https://doi.org/10.1042/CS20190654.
  6. Gottwick C., Carambia A., Herkel J. Harnessing the liver to induce antigen-specific immune tolerance. Semin Immunopathol. 2022; 44: 475–84. https://doi.org/10.1007/s00281-022-00942-8.
  7. Parlar Y.E., Ayar S.N., Cagdas D., Balaban Y.H. Liver immunity, autoimmunity, and inborn errors of immunity. World J. Hepatol. 2023; 15 (1): 52–67. doi: 10.4254/wjh.v15.i1.52.
  8. Rizvi S., Wang J., El-Khoueiry A.B. Liver Cancer Immunity. Hepatology. 2021; 73 (1): 86–103. doi: 10.1002/hep.31416.
  9. Yang Z.J. Innate immunity and early liver inflammation. Front Immunol. 2023; 14: 1175147. doi: 10.3389/fimmu.2023.1175147.
  10. Mikulak J., Bruni E., Oriolo F., Di Vito C., Mavilio D. Hepatic Natural Killer Cells: Organ-Specific Sentinels of Liver Immune Homeostasis and Physiopathology. Front Immunol. 2019; 10: 946. doi: 10.3389/fimmu.2019.00946.
  11. Zheng M., Tian Z. Liver-Mediated Adaptive Immune Tolerance. Front Immunol. 2019; 10: 2525. doi: 10.3389/fimmu.2019.02525.
  12. Sas Z., Cendrowicz E., Weinhäuser I., Rygiel T.P. Tumor Microenvironment of Hepatocellular Carcinoma: Challenges and Opportunities for New Treatment Options. Int J. Mol. Sci. 2022; 23 (7): 3778. doi: 10.3390/ijms23073778.
  13. Lu C., Rong D., Zhang B., Zheng W., Wang X., Chen Z., Tang W. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: challenges and opportunities. Mol. Cancer. 2019; 18 (1): 130. doi: 10.1186/s12943-019-1047-6.
  14. Wang S.Z., Lee S.D., Sarkar D., Lee H.M., Khan A., Bhati C., Sharma A., Kumaran V., Bruno D., Cotterell A., Levy M.F. Immunological characterization of hepatocellular carcinoma. Hepatoma Research. 2021; 7: 6. http://dx.doi.org/10.20517/2394-5079.2020.113.
  15. Xu X., Tan Y., Qian Y., Xue W., Wang Y., Du J., Jin L., Ding W. Clinicopathologic and prognostic significance of tumor-infiltrating CD8+ T-cells in patients with hepatocellular carcinoma: A meta-analysis. Medicine (Baltimore). 2019; 98 (2): e13923. doi: 10.1097/MD.0000000000013923.
  16. Stulpinas R., Zilenaite-Petrulaitiene D., Rasmusson A., Gulla A., Grigonyte A., Strupas K., Laurinavicius A. Prognostic Value of CD8+ Lymphocytes in Hepatocellular Carcinoma and Perineoplastic Parenchyma Assessed by Interface Density Profiles in Liver Resection Samples. Cancers (Basel). 2023; 15 (2): 366. doi: 10.3390/cancers15020366.
  17. Mossanen J.C., Kohlhepp M., Wehr A., Krenkel O., Liepelt A., Roeth A.A., Möckel D., Heymann F., Lammers T., Gassler N., Hermann J., Jankowski J., Neumann U.P., Luedde T., Trautwein C., Tacke F. CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4+ T-Cell-Dependent Control of Senescence. Gastroenterology. 2019; 156 (6): 1877–89.e4. doi: 10.1053/j.gastro.2019.01.247.
  18. Zander R., Schauder D., Xin G., Nguyen C., Wu X., Zajac A., Cui W. CD4+ T Cell Help Is Required for the Formation of a Cytolytic CD8+ T Cell Subset that Protects against Chronic Infection and Cancer. Immunity. 2019; 51 (6): 1028–42.e4. doi: 10.1016/j.immuni.2019.10.009.
  19. Yu S., Wang Y., Hou J., Li W., Wang X., Xiang L., Tan D., Wang W., Jiang L., Claret F.X., Jiao M., Guo H. Tumor-infiltrating immune cells in hepatocellular carcinoma: Tregs is correlated with poor overall survival. PLoS One. 2020; 15 (4): e0231003. doi: 10.1371/journal.pone.0231003.
  20. Largeot A., Pagano G., Gonder S., Moussay E., Paggetti J. The B-side of Cancer Immunity: The Underrated Tune. Cells. 2019; 8 (5): 449. doi: 10.3390/cells8050449.
  21. Qin M., Wang D., Fang Y., Zheng Z., Liu X., Wu F., Wang L., Li X., Hui B., Ma S., Tang W., Pan X. Current Perspectives on B Lymphocytes in the Immunobiology of Hepatocellular Carcinoma. Front Oncol. 2021; 11: 647854. doi: 10.3389/fonc.2021.647854.
  22. Zhang Z., Ma L., Goswami S., Ma J., Zheng B., Duan M., Liu L., Zhang L., Shi J., Dong L., Sun Y., Tian L., Gao Q., Zhang X. Landscape of infiltrating B cells and their clinical significance in human hepatocellular carcinoma. Oncoimmunology. 2019; 8 (4): e1571388. doi: 10.1080/2162402X.2019.1571388.
  23. Zhao M., Huang H., He F., Fu X. Current insights into the hepatic microenvironment and advances in immunotherapy for hepatocellular carcinoma. Front Immunol. 2023; 14: 1188277. doi: 10.3389/fimmu.2023.1188277.
  24. Hosseinzadeh F., Ai J., Ebrahimi-Barough S., Seyhoun I., Hajifathali A., Muhammadnejad S., Hosseinzadeh F., Shadnoush M., Dabiri Oskouei F., Verdi J. Natural Killer Cell Expansion with Autologous Feeder Layer and Anti-CD3 Antibody for Immune Cell Therapy of Hepatocellular Carcinoma. Asian Pac J. Cancer Prev. 2019; 20 (12): 3797–803. doi: 10.31557/APJCP.2019.20.12.3797.
  25. Sun H., Huang Q., Huang M., Wen H., Lin R., Zheng M., Qu K., Li K., Wei H., Xiao W., Sun R., Tian Z., Sun C. Human CD96 Correlates to Natural Killer Cell Exhaustion and Predicts the Prognosis of Human Hepatocellular Carcinoma. Hepatology. 2019; 70 (1): 168–83. doi: 10.1002/hep.30347.
  26. Sung P.S. Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma. Clin. Mol. Hepatol. 2022; 28 (3): 333–50. doi: 10.3350/cmh.2021.0308.
  27. Huang Y., Ge W., Zhou J., Gao B., Qian X., Wang W. The Role of Tumor Associated Macrophages in Hepatocellular Carcinoma. J. Cancer. 2021; 12 (5): 1284–94. doi: 10.7150/jca.51346.
  28. Cheng K., Cai N., Zhu J., Yang X., Liang H., Zhang W. Tumor-associated macrophages in liver cancer: From mechanisms to therapy. Cancer Commun (Lond). 2022; 42 (11): 1112–40. doi: 10.1002/cac2.12345.
  29. Peng X., He Y., Huang J., Tao Y., Liu S. Metabolism of Dendritic Cells in Tumor Microenvironment: For Immunotherapy. Front Immunol. 2021; 12: 613492. doi: 10.3389/fimmu.2021.613492.
  30. Peterson E.E., Barry K.C. The Natural Killer-Dendritic Cell Immune Axis in Anti-Cancer Immunity and Immunotherapy. Front Immunol. 2021; 11: 621254. doi: 10.3389/fimmu.2020.621254.
  31. Santos P.M., Menk A.V., Shi J., Tsung A., Delgoffe G.M., Butterfield L.H. Tumor-Derived α-Fetoprotein Suppresses Fatty Acid Metabolism and Oxidative Phosphorylation in Dendritic Cells. Cancer Immunol Res. 2019; 7 (6): 1001–12. doi: 10.1158/2326-6066.CIR-18-0513.
  32. Zhou Z.J., Xin H.Y., Li J., Hu Z.Q., Luo C.B., Zhou S.L. Intratumoral plasmacytoid dendritic cells as a poor prognostic factor for hepatocellular carcinoma following curative resection. Cancer Immunol Immunother. 2019; 68 (8): 1223–33. doi: 10.1007/s00262-019-02355-3.
  33. Niu Z.S., Wang W.H., Niu X.J. Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma. World J. Gastroenterol. 2022; 28 (46): 6433–77. doi: 10.3748/wjg.v28.i46.6433.
  34. Lurje I., Hammerich L., Tacke F. Dendritic Cell and T Cell Crosstalk in Liver Fibrogenesis and Hepatocarcinogenesis: Implications for Prevention and Therapy of Liver Cancer. Int J. Mol. Sci. 2020; 21 (19): 7378. doi: 10.3390/ijms21197378.
  35. Barry S.T., Gabrilovich D.I., Sansom O.J., Campbell A.D., Morton J.P. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer. 2023; 23 (4): 216–37. doi: 10.1038/s41568-022-00546-2.
  36. Ma T., Renz B.W., Ilmer M., Koch D., Yang Y., Werner J., Bazhin A.V. Myeloid-Derived Suppressor Cells in Solid Tumors. Cells. 2022; 11 (2): 310. doi: 10.3390/cells11020310
  37. Limagne E., Richard C., Thibaudin M., Fumet J.-D., Truntzer C., Lagrange A., Favier L., Coudert B., Ghiringhelli F. Tim-3/galectin-9 pathway and mMDSC control primary and secondary resistances to PD-1 blockade in lung cancer patients. Oncoimmunology. 2019; 8: e1564505. doi: 10.1080/2162402X.2018.1564505.
  38. An Y., Xu S., Liu Y., Xu X., Philips C.A., Chen J., Méndez-Sánchez N., Guo X., Qi X. Role of Galectins in the Liver Diseases: A Systematic Review and Meta-Analysis. Front Med (Lausanne). 2021; 8:744518. doi: 10.3389/fmed.2021.744518.
  39. Zhang X., Fu X., Li T., Yan H. The prognostic value of myeloid derived suppressor cell level in hepatocellular carcinoma: A systematic review and meta-analysis. PLoS One. 2019; 14 (12): e0225327. doi: 10.1371/journal.pone.0225327.
  40. Kundu D., Kennedy L., Meadows V., Baiocchi L., Alpini G., Francis H. The Dynamic Interplay Between Mast Cells, Aging/Cellular Senescence, and Liver Disease. Gene Expr. 2020; 20 (2): 77–88. doi: 10.3727/105221620X15960509906371.
  41. Huang S., Wu H., Luo F., Zhang B., Li T., Yang Z., Ren B., Yin W., Wu D., Tai S. Exploring the role of mast cells in the progression of liver disease. Front Physiol. 2022; 13: 964887. doi: 10.3389/fphys.2022.964887.
  42. Komi D.E.A., Redegeld F.A. Role of Mast Cells in Shaping the Tumor Microenvironment. Clin Rev Allergy Immunol. 2020; 58 (3): 313–25. doi: 10.1007/s12016-019-08753-w.
  43. Zhao J., Hou Y., Yin C., Hu J., Gao T., Huang X., Zhang X., Xing J., An J., Wan S., Li J. Upregulation of histamine receptor H1 promotes tumor progression and contributes to poor prognosis in hepatocellular carcinoma. Oncogene. 2020; 39 (8): 1724–38. doi: 10.1038/s41388-019-1093-y
  44. Yu D., Zhao J., Wang Y., Hu J., Zhao Q., Li J., Zhu J. Upregulated histamine receptor H3 promotes tumor growth and metastasis in hepatocellular carcinoma. Oncol Rep. 2019; 41 (6): 3347–54. doi: 10.3892/or.2019.7119.
  45. Arvanitakis K., Mitroulis I., Germanidis G. Tumor-Associated Neutrophils in Hepatocellular Carcinoma Pathogenesis, Prognosis, and Therapy. Cancers (Basel). 2021; 13 (12): 2899. doi: 10.3390/cancers13122899.
  46. Zahid K.R., Raza U., Tumbath S., Jiang L., Xu W., Huang X. Neutrophils: Musketeers against immunotherapy. Front Oncol. 2022; 12: 975981. doi: 10.3389/fonc.2022.975981.
  47. Zhou S.L., Yin D., Hu Z.Q., Luo C.B., Zhou Z.J., Xin H.Y., Yang X.R., Shi Y.H., Wang Z., Huang X.W., Cao Y., Fan J., Zhou J. A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression. Hepatology. 2019; 70 (4): 1214–30. doi: 10.1002/hep.30630.
  48. Schoenberg M.B., Li X., Li X., Han Y., Hao J., Miksch R.C., Koch D., Börner N., Beger N.T., Bucher J.N., Schiergens T.S., Guba M.O., Werner J., Bazhin A.V. The predictive value of tumor infiltrating leukocytes in Hepatocellular Carcinoma: A systematic review and meta-analysis. Eur. J. Surg Oncol. 2021; 47 (10): 2561–70. doi: 10.1016/j.ejso.2021.04.042.
  49. Yang L.Y., Luo Q., Lu L., Zhu W.W., Sun H.T., Wei R., Lin Z.F., Wang X.Y., Wang C.Q., Lu M., Jia H.L., Chen J.H., Zhang J.B., Qin L.X. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J. Hematol Oncol. 2020; 13 (1): 3. doi: 10.1186/s13045-019-0836-0.
  50. Zhu H.F., Feng J.K., Xiang Y.J., Wang K., Zhou L.P., Liu Z.H., Cheng Y.Q., Shi J., Guo W.X., Cheng S.Q. Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors. BMC Cancer. 2023; 23: 547 https://doi.org/10.1186/s12885-023-11003-0.
  51. Lin S., Hu S., Ran Y., Wu F. Neutrophil-to-lymphocyte ratio predicts prognosis of patients with hepatocellular carcinoma: a systematic review and meta-analysis. Transl Cancer Res. 2021; 10 (4): 1667–78. doi: 10.21037/tcr-20-3237.
  52. Bai J., Liang P., Li Q., Feng R., Liu J. Cancer Immunotherapy – Immune Checkpoint Inhibitors in Hepatocellular Carcinoma. Recent Pat Anticancer Drug Discov. 2021; 16 (2): 239–48. doi: 10.2174/1574892816666210212145107.
  53. Leone P., Solimando A.G., Fasano R., Argentiero A., Malerba E., Buonavoglia A., Lupo L.G., De Re V., Silvestris N., Racanelli V. The Evolving Role of Immune Checkpoint Inhibitors in Hepatocellular Carcinoma Treatment. Vaccines (Basel). 2021; 9 (5): 532. doi: 10.3390/vaccines9050532.
  54. Jácome A.A., Castro A.C.G., Vasconcelos J.P.S., Silva M.H.C.R., Lessa M.A.O., Moraes E.D., Andrade A.C., Lima F.M.T., Farias J.P.F., Gil R.A., Prolla G., Garicochea B. Efficacy and Safety Associated With Immune Checkpoint Inhibitors in Unresectable Hepatocellular Carcinoma: A Meta-analysis. JAMA Netw Open. 2021; 4 (12): e2136128. doi: 10.1001/jamanetworkopen.2021.36128
  55. Rao Q., Li M., Xu W., Pang K., Guo X., Wang D., Liu J., Guo W., Zhang Z. Clinical benefits of PD-1/PD-L1 inhibitors in advanced hepatocellular carcinoma: a systematic review and meta-analysis. Hepatol Int. 2020; 14 (5): 765–75. doi: 10.1007/s12072-020-10064-8.
  56. Makuku R., Khalili N., Razi S., Keshavarz-Fathi M., Rezaei N. Current and Future Perspectives of PD-1/PDL-1 Blockade in Cancer Immunotherapy. J. Immunol Res. 2021; 2021: 6661406. doi: 10.1155/2021/6661406.
  57. Liu J., Chen Z., Li Y., Zhao W., Wu J., Zhang Z. PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy. Front Pharmacol. 2021; 12: 731798. doi: 10.3389/fphar.2021.731798.
  58. Kudo M., Matilla A., Santoro A., Melero I., Gracián A.C., Acosta-Rivera M., Choo S.P., El-Khoueiry A.B., Kuromatsu R., El-Rayes B., Numata K., Itoh Y., Di Costanzo F., Crysler O., Reig M., Shen Y., Neely J., Tschaika M., Wisniewski T., Sangro B. CheckMate 040 cohort 5: A phase I/II study of nivolumab in patients with advanced hepatocellular carcinoma and Child-Pugh B cirrhosis. J. Hepatol. 2021; 75 (3): 600–9. doi: 10.1016/j.jhep.2021.04.047.
  59. Yau T., Park J.W., Finn R.S., Cheng A.L., Mathurin P., Edeline J., Kudo M., Harding J.J., Merle P., Rosmorduc O., Wyrwicz L., Schott E., Choo S.P., Kelley R.K., Sieghart W., Assenat E., Zaucha R., Furuse J., Abou-Alfa G.K., El-Khoueiry A.B., Melero I., Begic D., Chen G., Neely J., Wisniewski T., Tschaika M., Sangro B. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022; 23 (1): 77–90. doi: 10.1016/S1470-2045(21)00604-5.
  60. Finn R.S., Ryoo B.Y., Merle P., Kudo M., Bouattour M., Lim H.Y., Breder V., Edeline J., Chao Y., Ogasawara S., Yau T., Garrido M., Chan S.L., Knox J., Daniele B., Ebbinghaus S.W., Chen E., Siegel A.B., Zhu A.X., Cheng A.L. KEYNOTE-240 investigators. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J. Clin. Oncol. 2020; 38 (3): 193–202. doi: 10.1200/JCO.19.01307
  61. Desai J., Deva S., Lee J.S., Lin C.C., Yen C.J., Chao Y., Keam B., Jameson M., Hou M.M., Kang Y.K., Markman B., Lu C.H., Rau K.M., Lee K.H., Horvath L., Friedlander M., Hill A., Sandhu S., Barlow P., Wu C.Y., Zhang Y., Liang L., Wu J., Paton V., Millward M. Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. J. Immunother Cancer. 2020; 8 (1): e000453. doi: 10.1136/jitc-2019-000453.
  62. Qin S., Finn R.S., Kudo M., Meyer T., Vogel A., Ducreux M., Macarulla T.M., Tomasello G., Boisserie F., Hou J., Li X., Song J., Zhu A.X. RATIONALE 301 study: tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. Future Oncol. 2019; 15 (16): 1811–22. doi: 10.2217/fon-2019-0097.
  63. Qin S., Ren Z., Meng Z., Chen Z., Chai X., Xiong J., Bai Y., Yang L., Zhu H., Fang W., Lin X., Chen X., Li E., Wang L., Chen C., Zou J. Camrelizumab in patients with previously treated advanced hepatocellular carcinoma: a multicentre, open-label, parallel-group, randomised, phase 2 trial. Lancet Oncol. 2020; 21 (4): 571–80. doi: 10.1016/S1470-2045(20)30011-5.
  64. Kudo M. Scientific Rationale for Combination Immunotherapy of Hepatocellular Carcinoma with Anti-PD-1/PD-L1 and Anti-CTLA-4 Antibodies. Liver Cancer. 2019; 8 (6): 413–26. doi: 10.1159/000503254.
  65. Agdashian D., ElGindi M., Xie C., Sandhu M., Pratt D., Kleiner D.E., Figg W.D., Rytlewski J.A., Sanders C., Yusko E.C., Wood B., Venzon D., Brar G., Duffy A.G., Greten T.F., Korangy F. The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T-cells in patients with hepatocellular carcinoma. Cancer Immunol Immunother. 2019; 68 (4): 599–608. doi: 10.1007/s00262-019-02299-8.
  66. Cheng H., Sun G., Chen H., Li Y., Han Z., Li Y., Zhang P., Yang L., Li Y. Trends in the treatment of advanced hepatocellular carcinoma: immune checkpoint blockade immunotherapy and related combination therapies. Am. J. Cancer Res. 2019; 9 (8): 1536–45.
  67. Ganjalikhani Hakemi M., Jafarinia M., Azizi M., Rezaeepoor M., Isayev O., Bazhin A.V. The Role of TIM-3 in Hepatocellular Carcinoma: A Promising Target for Immunotherapy? Front Oncol. 2020; 10: 601661. doi: 10.3389/fonc.2020.601661.
  68. Hu S., Liu X., Li T., Li Z., Hu F. LAG3 (CD223) and autoimmunity: Emerging evidence. J. Autoimmun. 2020; 112: 102504. doi: 10.1016/j.jaut.2020.102504.
  69. Yau T., Zagonel V., Santoro A., Acosta-Rivera M., Choo S.P., Matilla A., He A.R., Cubillo Gracian A., El-Khoueiry A.B., Sangro B., Eldawy T.E., Bruix J., Frassineti G.L., Vaccaro G.M., Tschaika M., Scheffold C., Koopmans P., Neely J., Piscaglia F. Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. J. Clin. Oncol. 2023; 41 (9): 1747–57. doi: 10.1200/JCO.22.00972.
  70. Abou-Alfa G.K., Chan S.L., Kudo M., Lau G., Kelley R.K., Furuse J., Sukeepaisarnjaroen W., Kang Y.-K., Dao T.V., De Toni E.N., Enrico N. De Toni, Rimassa L., Breder V.V., Vasilyev A., Heurgue A., Tam V., Mody K., Thungappa S.C., He P., Negro A., Sangro B. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J. Clin. Oncol. 2022; 40 (S4): 379. doi: 10.1200/JCO.2022.40.4_suppl.379.
  71. Tamura R., Tanaka T., Akasaki Y., Murayama Y., Yoshida K., Sasaki H. The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications. Med Oncol. 2019; 37 (1): 2. doi: 10.1007/s12032-019-1329-2.
  72. Cheng A.L., Qin S., Ikeda M., Galle P.R., Ducreux M., Kim T.Y., Lim H.Y., Kudo M., Breder V., Merle P., Kaseb A.O., Li D., Verret W., Ma N., Nicholas A., Wang Y., Li L., Zhu A.X., Finn R.S. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J. Hepatol. 2022; 76 (4): 862–73. doi: 10.1016/j.jhep.2021.11.030.
  73. Ren Z., Xu J., Bai Y., Xu A., Cang S., Du C., Li Q., Lu Y., Chen Y., Guo Y., Chen Z., Liu B., Jia W., Wu J., Wang J., Shao G., Zhang B., Shan Y., Meng Z., Wu J., Gu S., Yang W., Liu C., Shi X., Gao Z., Yin T., Cui J., Huang M., Xing B., Mao Y., Teng G., Qin Y., Wang J., Xia F., Yin G., Yang Y., Chen M., Wang Y., Zhou H., Fan J. ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021; 22 (7): 977–90. doi: 10.1016/S1470-2045(21)00252-7.
  74. Ju S., Zhou C., Yang C., Wang C., Liu J., Wang Y., Huang S., Li T., Chen Y., Bai Y., Yao W., Xiong B. Apatinib Plus Camrelizumab With /Without Chemoembolization for Hepatocellular Carcinoma: A Real-World Experience of a Single Center. Front Oncol. 2022; 11: 835889. doi: 10.3389/fonc.2021.835889.
  75. Finn R.S., Ikeda M., Zhu A.X., Sung M.W., Baron A.D., Kudo M., Okusaka T., Kobayashi M., Kumada H., Kaneko S., Pracht M., Mamontov K., Meyer T., Kubota T., Dutcus C.E., Saito K., Siegel A.B., Dubrovsky L., Mody K., Llovet J.M. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J. Clin Oncol. 2020; 38 (26): 2960–70. doi: 10.1200/JCO.20.00808.
  76. Li J., Xuan S., Dong P., Xiang Z., Gao C., Li M., Huang L., Wu J. Immunotherapy of hepatocellular carcinoma: recent progress and new strategy. Front Immunol. 2023; 14: 1192506. doi: 10.3389/fimmu.2023.1192506.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Schematic representation of the cellular composition, cytokines, chemokines, and immune microenvironmental checkpoint molecules in progressive HCC

Download (138KB)
Indexing metadata
3. Fig. 2. Schematic representation of immune checkpoints as targets for immunotherapy in HCC

Download (307KB)
Indexing metadata

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies