REFERENCES
2. Arnold M, Abnet CC, Neale RE, et al. Global burden of 5 major types of gastrointestinal cancer. Gastroenterology 2020;159:335-49.e15.
3. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21.
4. Petrick JL, Florio AA, Znaor A, et al. International trends in hepatocellular carcinoma incidence, 1978-2012. Int J Cancer 2020;147:317-30.
5. Arvanitakis K, Koletsa T, Mitroulis I, Germanidis G. Tumor-associated macrophages in hepatocellular carcinoma pathogenesis, prognosis and therapy. Cancers 2022;14:226.
6. Arvanitakis K, Mitroulis I, Chatzigeorgiou A, Elefsiniotis I, Germanidis G. The liver cancer immune microenvironment: emerging concepts for myeloid cell profiling with diagnostic and therapeutic implications. Cancers 2023;15:1522.
7. Arvanitakis K, Mitroulis I, Germanidis G. Tumor-associated neutrophils in hepatocellular carcinoma pathogenesis, prognosis, and therapy. Cancers 2021;13:2899.
8. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology 2021;73 Suppl 1:4-13.
9. Jinjuvadia R, Patel S, Liangpunsakul S. The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 2014;48:172-7.
10. Bouvard V, Baan R, Straif K, et al. WHO International Agency for Research on Cancer Monograph Working Group. A review of human carcinogens--part B: biological agents. Lancet Oncol 2009;10:321-2.
11. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis. J Carcinog 2017;16:1.
12. Caruso S, O'Brien DR, Cleary SP, Roberts LR, Zucman-Rossi J. Genetics of hepatocellular carcinoma: approaches to explore molecular diversity. Hepatology 2021;73 Suppl 1:14-26.
13. Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015;47:505-11.
14. Meunier L, Hirsch TZ, Caruso S, et al. DNA methylation signatures reveal the diversity of processes remodeling hepatocellular carcinoma methylomes. Hepatology 2021;74:816-34.
15. De Sousa Linhares A, Leitner J, Grabmeier-Pfistershammer K, Steinberger P. Not all immune checkpoints are created equal. Front Immunol 2018;9:1909.
16. Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol 2018;18:153-67.
18. Triebel F, Jitsukawa S, Baixeras E, et al. LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med 1990;171:1393-405.
19. Wang J, Sanmamed MF, Datar I, et al. Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 2019;176:334-47.e12.
20. Lichtenegger FS, Rothe M, Schnorfeil FM, et al. Targeting LAG-3 and PD-1 to enhance T cell activation by antigen-presenting cells. Front Immunol 2018;9:385.
21. Ming Q, Celias DP, Wu C, et al. LAG3 ectodomain structure reveals functional interfaces for ligand and antibody recognition. Nat Immunol 2022;23:1031-41.
22. Guy C, Mitrea DM, Chou PC, et al. LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation. Nat Immunol 2022;23:757-67.
23. Huard B, Mastrangeli R, Prigent P, et al. Characterization of the major histocompatibility complex class II binding site on LAG-3 protein. Proc Natl Acad Sci U S A 1997;94:5744-9.
24. Workman CJ, Vignali DA. The CD4-related molecule, LAG-3 (CD223), regulates the expansion of activated T cells. Eur J Immunol 2003;33:970-9.
25. Annunziato F, Manetti R, Tomasévic I, et al. Expression and release of LAG-3-encoded protein by human CD4+ T cells are associated with IFN-gamma production . FASEB J 1996;10:769-76.
26. Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA. Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol 2004;172:5450-5.
27. Bruniquel D, Borie N, Hannier S, Triebel F. Regulation of expression of the human lymphocyte activation gene-3 (LAG-3) molecule, a ligand for MHC class II. Immunogenetics 1998;48:116-24.
28. Burton BR, Britton GJ, Fang H, et al. Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy. Nat Commun 2014;5:4741.
29. Workman C, Rice D, Dugger K, Kurschner C, Vignali D. Phenotypic analysis of the murine CD4-related glycoprotein, CD223 (LAG-3). Eur J Immunol ;32:2255.
30. Long L, Zhang X, Chen F, et al. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. Genes Cancer 2018;9:176-89.
31. Huard B, Prigent P, Tournier M, Bruniquel D, Triebel F. CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur J Immunol 1995;25:2718-21.
32. Liang B, Workman C, Lee J, et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 2008;180:5916-26.
33. Hemon P, Jean-Louis F, Ramgolam K, et al. MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol 2011;186:5173-83.
34. Donia M, Andersen R, Kjeldsen JW, et al. Aberrant expression of MHC class II in melanoma attracts inflammatory tumor-specific CD4+ T- Cells, which dampen CD8+ T-cell antitumor reactivity. Cancer Res 2015;75:3747-59.
35. Wherry EJ, Ha SJ, Kaech SM, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 2007;27:670-84.
36. Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta 2006;1760:616-35.
37. Kouo T, Huang L, Pucsek AB, et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res 2015;3:412-23.
38. Liu W, Tang L, Zhang G, et al. Characterization of a novel C-type lectin-like gene, LSECtin: demonstration of carbohydrate binding and expression in sinusoidal endothelial cells of liver and lymph node. J Biol Chem 2004;279:18748-58.
39. Xu F, Liu J, Liu D, et al. LSECtin expressed on melanoma cells promotes tumor progression by inhibiting antitumor T-cell responses. Cancer Res 2014;74:3418-28.
40. Rimassa L, Finn RS, Sangro B. Combination immunotherapy for hepatocellular carcinoma. J Hepatol 2023;79:506-15.
41. Kisielow M, Kisielow J, Capoferri-Sollami G, Karjalainen K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur J Immunol 2005;35:2081-8.
42. Workman CJ, Vignali DA. Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol 2005;174:688-95.
43. Brignone C, Grygar C, Marcu M, Schäkel K, Triebel F. A soluble form of lymphocyte activation gene-3 (IMP321) induces activation of a large range of human effector cytotoxic cells. J Immunol 2007;179:4202-11.
44. Prigent P, El mir S, Dréano M, Triebel F. Lymphocyte activation gene-3 induces tumor regression and antitumor immune responses. Eur J Immunol 1999;29:3867-76.
45. Casati C, Camisaschi C, Rini F, et al. Soluble human LAG-3 molecule amplifies the in vitro generation of type 1 tumor-specific immunity. Cancer Res 2006;66:4450-60.
46. Triebel F, Hacene K, Pichon MF. A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors. Cancer Lett 2006;235:147-53.
48. Machairas N, Tsilimigras DI, Pawlik TM. Current landscape of immune checkpoint inhibitor therapy for hepatocellular carcinoma. Cancers 2022;14:2018.
49. Tawbi HA, Schadendorf D, Lipson EJ, et al. RELATIVITY-047 Investigators. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med 2022;386:24-34.
51. Aggarwal V, Workman CJ, Vignali DAA. LAG-3 as the third checkpoint inhibitor. Nat Immunol 2023;24:1415-22.
52. El-Khoueiry AB, Sangro B, Yau T, 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 2017;389:2492-502.
53. Minaei N, Ramezankhani R, Tamimi A, et al. Immunotherapeutic approaches in Hepatocellular carcinoma: building blocks of hope in near future. Eur J Cell Biol 2023;102:151284.
54. Ruff SM, Manne A, Cloyd JM, Dillhoff M, Ejaz A, Pawlik TM. Current landscape of immune checkpoint inhibitor therapy for hepatocellular carcinoma. Curr Oncol 2023;30:5863-75.
55. Hage C, Hoves S, Ashoff M, et al. Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy. PLoS One 2019;14:e0219517.
56. Voron T, Colussi O, Marcheteau E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 2015;212:139-48.
57. Ziogas AC, Gavalas NG, Tsiatas M, et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer 2012;130:857-64.
58. Fu Z, Mowday AM, Smaill JB, Hermans IF, Patterson AV. Tumour hypoxia-mediated immunosuppression: mechanisms and therapeutic approaches to improve cancer immunotherapy. Cells 2021;10:1006.
59. Sarcognato S, García-Lezana T, Villanueva A. Mechanisms of action of drugs effective in hepatocellular carcinoma. Clin Liver Dis 2019;14:62-5.
60. Cabrera R, Ararat M, Xu Y, et al. Immune modulation of effector CD4+ and regulatory T cell function by sorafenib in patients with hepatocellular carcinoma. Cancer Immunol Immunother 2013;62:737-46.
61. Esteban-Fabró R, Willoughby CE, Piqué-Gili M, et al. Cabozantinib enhances anti-PD1 activity and elicits a neutrophil-based immune response in hepatocellular carcinoma. Clin Cancer Res 2022;28:2449-60.
62. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022;76:681-93.
63. Chew V, Tow C, Teo M, et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 2010;52:370-9.
64. Foerster F, Gairing SJ, Ilyas SI, Galle PR. Emerging immunotherapy for HCC: a guide for hepatologists. Hepatology 2022;75:1604-26.
65. Pedroza-Gonzalez A, Verhoef C, Ijzermans JN, et al. Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer. Hepatology 2013;57:183-94.
66. Nguyen LT, Ohashi PS. Clinical blockade of PD1 and LAG3--potential mechanisms of action. Nat Rev Immunol 2015;15:45-56.
67. Yang C, Qian Q, Zhao Y, et al. Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma. Front Immunol 2023;14:1112672.
68. Woo SR, Turnis ME, Goldberg MV, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 2012;72:917-27.
69. Zhou G, Sprengers D, Boor PPC, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology 2017;153:1107-19.e10.
70. Guo M, Yuan F, Qi F, et al. Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8+T cells in hepatocellular carcinoma using multiplex quantitative analysis. J Transl Med 2020;18:306.
71. Ascierto P, Bono P, Bhatia S, et al. Efficacy of BMS-986016, a monoclonal antibody that targets lymphocyte activation gene-3 (LAG-3), in combination with nivolumab in pts with melanoma who progressed during prior anti-PD-1/PD-L1 therapy (mel prior IO) in all-comer and biomarker-enriched populations. Ann Oncol 2017;28:v611-2.
72. Wang J, Wei W, Tang Q, et al. Oxysophocarpine suppresses hepatocellular carcinoma growth and sensitizes the therapeutic blockade of anti-Lag-3 via reducing FGL1 expression. Cancer Med 2020;9:7125-36.
73. Tian J, Liu Y, Zhang TL, et al. Clinical significance of LAG-3 on microvessel density in primary hepatocellular carcinoma. Indian J Pathol Microbiol 2022;65:581-8.
74. Cheung CCL, Seah YHJ, Fang J, et al. Immunohistochemical scoring of LAG-3 in conjunction with CD8 in the tumor microenvironment predicts response to immunotherapy in hepatocellular carcinoma. Front Immunol 2023;14:1150985.
75. Guo M, Qi F, Rao Q, et al. Serum LAG-3 predicts outcome and treatment response in hepatocellular carcinoma patients with transarterial chemoembolization. Front Immunol 2021;12:754961.
76. Yang SF, Weng MT, Liang JD, et al. Neoantigen vaccination augments antitumor effects of anti-PD-1 on mouse hepatocellular carcinoma. Cancer Lett 2023;563:216192.
77. Jia J, Ga L, Liu Y, et al. Serine protease inhibitor Kazal type 1, a potential biomarker for the early detection, targeting, and prediction of response to immune checkpoint blockade therapies in hepatocellular carcinoma. Front Immunol 2022;13:923031.
78. Li Y, Song Z, Han Q, et al. Targeted inhibition of STAT3 induces immunogenic cell death of hepatocellular carcinoma cells via glycolysis. Mol Oncol 2022;16:2861-80.
79. Macek Jilkova Z, Aspord C, Kurma K, et al. Immunologic features of patients with advanced hepatocellular carcinoma before and during sorafenib or anti-programmed death-1/programmed death-l1 treatment. Clin Transl Gastroenterol 2019;10:e00058.
80. Deng WW, Mao L, Yu GT, et al. LAG-3 confers poor prognosis and its blockade reshapes antitumor response in head and neck squamous cell carcinoma. Oncoimmunology 2016;5:e1239005.
81. Burugu S, Gao D, Leung S, Chia SK, Nielsen TO. LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors. Ann Oncol 2017;28:2977-84.
82. Que Y, Fang Z, Guan Y, et al. LAG-3 expression on tumor-infiltrating T cells in soft tissue sarcoma correlates with poor survival. Cancer Biol Med 2019;16:331-40.
83. He Y, Yu H, Rozeboom L, et al. LAG-3 protein expression in non-small cell lung cancer and its relationship with PD-1/PD-L1 and tumor-infiltrating lymphocytes. J Thorac Oncol 2017;12:814-23.
84. Zhang Y, Liu YD, Luo YL, et al. Prognostic value of lymphocyte activation gene-3 (LAG-3) expression in esophageal squamous cell carcinoma. J Cancer 2018;9:4287-93.
85. Hald SM, Rakaee M, Martinez I, et al. LAG-3 in non-small-cell lung cancer: expression in primary tumors and metastatic lymph nodes is associated with improved survival. Clin Lung Cancer 2018;19:249-59.e2.
86. Shepherd DJ, Tabb ES, Kunitoki K, et al. Lymphocyte-activation gene 3 in non-small-cell lung carcinomas: correlations with clinicopathologic features and prognostic significance. Mod Pathol 2022;35:615-24.
87. Sangro B, Numata K, Huang Y, et al. P-61 Relatlimab + nivolumab in patients with advanced hepatocellular carcinoma who are naive to immuno-oncology therapy but progressed on tyrosine kinase inhibitors, a phase 2, randomized, open-label study: RELATIVITY-073. Ann Oncol 2021;32:S117.
88. Sangro B, Melero I, Wadhawan S, et al. Association of inflammatory biomarkers with clinical outcomes in nivolumab-treated patients with advanced hepatocellular carcinoma. J Hepatol 2020;73:1460-9.
89. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci U S A 2010;107:7875-80.
90. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory pathways in immunotherapy for cancer. Annu Rev Immunol 2016;34:539-73.
91. Bie F, Wang G, Qu X, et al. Loss of FGL1 induces epithelial-mesenchymal transition and angiogenesis in LKB1 mutant lung adenocarcinoma. Int J Oncol 2019;55:697-707.
92. Nayeb-Hashemi H, Desai A, Demchev V, et al. Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development. Biochem Biophys Res Commun 2015;465:167-73.
