Chronic Inflammatory and Immune Microenvironment Promote Hepatocellular Carcinoma Evolution

References

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. doi:10.3322/caac.21492
   PubMed Web of Science ®Google Scholar
• Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular Carcinoma. Gastroenterology. 2019;156(2):477–491.e471. doi:10.1053/j.gastro.2018.08.065
   PubMed Web of Science ®Google Scholar
• Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1–61. doi:10.1016/bs.acr.2020.10.001
   PubMed Web of Science ®Google Scholar
• Woolbright BL, Jaeschke H. Sterile inflammation in acute liver injury: myth or mystery? Expert Rev Gastroenterol Hepatol. 2015;9(8):1027–1029. doi:10.1586/17474124.2015.1060855
   PubMed Web of Science ®Google Scholar
• Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res. 2014;2014:149185. doi:10.1155/2014/149185
   PubMed Web of Science ®Google Scholar
• Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer. 2003;3(4):276–285. doi:10.1038/nrc1046
   PubMed Web of Science ®Google Scholar
• Winrow VR, Winyard PG, Morris CJ, Blake DR. Free radicals in inflammation: second messengers and mediators of tissue destruction. Br Med Bull. 1993;49(3):506–522. doi:10.1093/oxfordjournals.bmb.a072627
   PubMed Web of Science ®Google Scholar
• Rosen GM, Pou S, Ramos CL, Cohen MS, Britigan BE. Free radicals and phagocytic cells. FASEB J. 1995;9(2):200–209. doi:10.1096/fasebj.9.2.7540156
   PubMed Web of Science ®Google Scholar
• Yang D, Elner SG, Bian ZM, Till GO, Petty HR, Elner VM. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res. 2007;85(4):462–472. doi:10.1016/j.exer.2007.06.013
   PubMed Web of Science ®Google Scholar
• Han F, Li S, Yang Y, Bai Z. Interleukin-6 promotes ferroptosis in bronchial epithelial cells by inducing reactive oxygen species-dependent lipid peroxidation and disrupting iron homeostasis. Bioengineered. 2021;12(1):5279–5288. doi:10.1080/21655979.2021.1964158
   PubMed Web of Science ®Google Scholar
• Ferlat S, Favier A. Tumor necrosis factor (TNF) and oxygen free radicals: potential effects for immunity. C R Seances Soc Biol Fil. 1993;187(3):296–307.
   PubMedGoogle Scholar
• Crosas-Molist E, Bertran E, Fabregat I. Cross-talk between TGF-β and NADPH oxidases during liver fibrosis and hepatocarcinogenesis. Curr Pharm Des. 2015;21(41):5964–5976. doi:10.2174/1381612821666151029112126
   PubMed Web of Science ®Google Scholar
• Lee HY, Nga HT, Tian J, Yi HS. Mitochondrial metabolic signatures in hepatocellular carcinoma. Cells. 2021;10(8). doi:10.3390/cells10081901
   Web of Science ®Google Scholar
• Jaiswal M, LaRusso NF, Shapiro RA, Billiar TR, Gores GJ. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. Gastroenterology. 2001;120(1):190–199. doi:10.1053/gast.2001.20875
   PubMed Web of Science ®Google Scholar
• Hofseth LJ, Saito S, Hussain SP, et al. Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc Natl Acad Sci U S A. 2003;100(1):143–148. doi:10.1073/pnas.0237083100
   PubMed Web of Science ®Google Scholar
• Ambs S, Merriam WG, Ogunfusika MO, et al. p53 and vascular endothelial growth factor regulate tumor growth of NOS2-expressing human carcinoma cells. Nat Med. 1998;4(12):1371–1376. doi:10.1038/3957
   PubMed Web of Science ®Google Scholar
• Zamarron BF, Chen W. Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci. 2011;7(5):651–658. doi:10.7150/ijbs.7.651
   PubMed Web of Science ®Google Scholar
• Havell EA, Fiers W, North RJ. The antitumor function of tumor necrosis factor (TNF), I. Therapeutic action of TNF against an established murine sarcoma is indirect, immunologically dependent, and limited by severe toxicity. J Exp Med. 1988;167(3):1067–1085. doi:10.1084/jem.167.3.1067
   PubMed Web of Science ®Google Scholar
• Zidi I, Mestiri S, Bartegi A, Amor NB. TNF-alpha and its inhibitors in cancer. Med Oncol. 2010;27(2):185–198. doi:10.1007/s12032-009-9190-3
   PubMed Web of Science ®Google Scholar
• Balkwill F. TNF-alpha in promotion and progression of cancer. Cancer Metastasis Rev. 2006;25(3):409–416. doi:10.1007/s10555-006-9005-3
   PubMed Web of Science ®Google Scholar
• Cubero FJ, Zhao G, Nevzorova YA, et al. Haematopoietic cell-derived Jnk1 is crucial for chronic inflammation and carcinogenesis in an experimental model of liver injury. J Hepatol. 2015;62(1):140–149. doi:10.1016/j.jhep.2014.08.029
   PubMed Web of Science ®Google Scholar
• Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol. 2016;64(6):1403–1415. doi:10.1016/j.jhep.2016.02.004
   PubMed Web of Science ®Google Scholar
• Aleksandrova K, Boeing H, Nöthlings U, et al. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology. 2014;60(3):858–871. doi:10.1002/hep.27016
   PubMed Web of Science ®Google Scholar
• Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol. 2014;26(1):54–74. doi:10.1016/j.smim.2014.01.001
   PubMed Web of Science ®Google Scholar
• Weber R, Groth C, Lasser S, et al. IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cell Immunol. 2021;359:104254. doi:10.1016/j.cellimm.2020.104254
   PubMed Web of Science ®Google Scholar
• Wan S, Zhao E, Kryczek I, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology. 2014;147(6):1393–1404. doi:10.1053/j.gastro.2014.08.039
   PubMed Web of Science ®Google Scholar
• Fabregat I, Moreno-Càceres J, Sánchez A, et al. TGF-β signalling and liver disease. Febs j. 2016;283(12):2219–2232. doi:10.1111/febs.13665
   PubMed Web of Science ®Google Scholar
• Xu J, Lamouille S, Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 2009;19(2):156–172. doi:10.1038/cr.2009.5
   PubMed Web of Science ®Google Scholar
• Chen J, Gingold JA, Su X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma. Trends Mol Med. 2019;25(11):1010–1023. doi:10.1016/j.molmed.2019.06.007
   PubMed Web of Science ®Google Scholar
• Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS. Interleukin-10 signaling blocks inhibitor of kappaB kinase activity and nuclear factor kappaB DNA binding. J Biol Chem. 1999;274(45):31868–31874. doi:10.1074/jbc.274.45.31868
   PubMed Web of Science ®Google Scholar
• Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 2015;367(2):103–107. doi:10.1016/j.canlet.2015.07.009
   PubMed Web of Science ®Google Scholar
• Campana L, Starkey Lewis PJ, Pellicoro A, et al. The STAT3-IL-10-IL-6 pathway is a novel regulator of macrophage efferocytosis and phenotypic conversion in sterile liver injury. J Immunol. 2018;200(3):1169–1187. doi:10.4049/jimmunol.1701247
   PubMed Web of Science ®Google Scholar
• El-Emshaty HM, Nasif WA, Mohamed IE. Serum cytokine of IL-10 and IL-12 in chronic liver disease: the immune and inflammatory response. Dis Markers. 2015;2015:707254. doi:10.1155/2015/707254
   PubMed Web of Science ®Google Scholar
• Morse MA, Sun W, Kim R, et al. The role of angiogenesis in hepatocellular carcinoma. Clin Cancer Res. 2019;25(3):912–920. doi:10.1158/1078-0432.CCR-18-1254
   PubMed Web of Science ®Google Scholar
• Li H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol. 2021;15(3):217–233. doi:10.1080/17474124.2021.1842732
   PubMed Web of Science ®Google Scholar
• Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 2004;64(11):3731–3736. doi:10.1158/0008-5472.CAN-04-0074
   PubMed Web of Science ®Google Scholar
• Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res. 2019;25(18):5449–5457. doi:10.1158/1078-0432.CCR-18-1543
   PubMed Web of Science ®Google Scholar
• Kukla M. Angiogenesis: a phenomenon which aggravates chronic liver disease progression. Hepatol Int. 2013;7(1):4–12. doi:10.1007/s12072-012-9391-2
   PubMed Web of Science ®Google Scholar
• Zhou W, Yang L, Nie L, Lin H. Unraveling the molecular mechanisms between inflammation and tumor angiogenesis. Am J Cancer Res. 2021;11(2):301–317.
   PubMed Web of Science ®Google Scholar
• Paternostro C, David E, Novo E, Parola M. Hypoxia, angiogenesis and liver fibrogenesis in the progression of chronic liver diseases. World J Gastroenterol. 2010;16(3):281–288. doi:10.3748/wjg.v16.i3.281
   PubMed Web of Science ®Google Scholar
• Kim YW, West XZ, Byzova TV. Inflammation and oxidative stress in angiogenesis and vascular disease. J Mol Med. 2013;91(3):323–328. doi:10.1007/s00109-013-1007-3
   PubMed Web of Science ®Google Scholar
• Kroll J, Waltenberger J. Regulation of the endothelial function and angiogenesis by vascular endothelial growth factor-A (VEGF-A. Z Kardiol. 2000;89(3):206–218. doi:10.1007/s003920050472
   PubMedGoogle Scholar
• Coulon S, Heindryckx F, Geerts A, Van Steenkiste C, Colle I, Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int. 2011;31(2):146–162. doi:10.1111/j.1478-3231.2010.02369.x
   PubMed Web of Science ®Google Scholar
• Bottazzi B, Riboli E, Mantovani A. Aging, inflammation and cancer. Semin Immunol. 2018;40:74–82. doi:10.1016/j.smim.2018.10.011
   PubMed Web of Science ®Google Scholar
• Hager K, Machein U, Krieger S, Platt D, Seefried G, Bauer J. Interleukin-6 and selected plasma proteins in healthy persons of different ages. Neurobiol Aging. 1994;15(6):771–772. doi:10.1016/0197-4580(94)90066-3
   PubMed Web of Science ®Google Scholar
• Michaud M, Balardy L, Moulis G, et al. Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc. 2013;14(12):877–882. doi:10.1016/j.jamda.2013.05.009
   PubMed Web of Science ®Google Scholar
• Chung HY, Lee EK, Choi YJ, et al. Molecular inflammation as an underlying mechanism of the aging process and age-related diseases. J Dent Res. 2011;90(7):830–840. doi:10.1177/0022034510387794
   PubMed Web of Science ®Google Scholar
• Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med. 2005;2(1):29–36; quiz 58. doi:10.1038/ncpcardio0074
   PubMedGoogle Scholar
• Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–254. doi:10.1111/j.1749-6632.2000.tb06651.x
   PubMed Web of Science ®Google Scholar
• Vasto S, Candore G, Balistreri CR, et al. Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev. 2007;128(1):83–91. doi:10.1016/j.mad.2006.11.015
   PubMed Web of Science ®Google Scholar
• Mohammed S, Thadathil N, Selvarani R, et al. Necroptosis contributes to chronic inflammation and fibrosis in aging liver. Aging Cell. 2021;20(12):e13512. doi:10.1111/acel.13512
   PubMed Web of Science ®Google Scholar
• Kubes P, Jenne C. Immune Responses in the Liver. Annu Rev Immunol. 2018;36:247–277. doi:10.1146/annurev-immunol-051116-052415
   PubMed Web of Science ®Google Scholar
• Liaskou E, Wilson DV, Oo YH. Innate immune cells in liver inflammation. Mediators Inflamm. 2012;2012:949157. doi:10.1155/2012/949157
   PubMed Web of Science ®Google Scholar
• Song M, He J, Pan QZ, et al. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology. 2021;73(5):1717–1735. doi:10.1002/hep.31792
   PubMed Web of Science ®Google Scholar
• Zhou Y, Ren H, Dai B, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts. J Exp Clin Cancer Res. 2018;37(1):324. doi:10.1186/s13046-018-0965-2
   PubMed Web of Science ®Google Scholar
• Huang P, Kong Q, Gao W, et al. Spatial proteome profiling by immunohistochemistry-based laser capture microdissection and data-independent acquisition proteomics. Anal Chim Acta. 2020;1127:140–148. doi:10.1016/j.aca.2020.06.049
   PubMed Web of Science ®Google Scholar
• Zhang J, Gu C, Song Q, et al. Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma. Cell Biosci. 2020;10(1):127. doi:10.1186/s13578-020-00488-y
   PubMed Web of Science ®Google Scholar
• Huang B, Huang M, Li Q. Cancer-associated fibroblasts promote angiogenesis of hepatocellular carcinoma by VEGF-Mediated EZH2/VASH1 pathway. Technol Cancer Res Treat. 2019;18:1533033819879905. doi:10.1177/1533033819879905
   Web of Science ®Google Scholar
• Liu Z, Chen M, Zhao R, et al. CAF-induced placental growth factor facilitates neoangiogenesis in hepatocellular carcinoma. Acta Biochim Biophys Sin. 2020;52(1):18–25. doi:10.1093/abbs/gmz134
   Google Scholar
• Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–1428. doi:10.1172/JCI39104
   PubMed Web of Science ®Google Scholar
• Li T, Yang Y, Hua X, et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012;318(2):154–161. doi:10.1016/j.canlet.2011.12.020
   PubMed Web of Science ®Google Scholar
• Yang F, Wei Y, Han D, et al. Interaction with CD68 and regulation of GAS6 expression by endosialin in fibroblasts drives recruitment and polarization of macrophages in hepatocellular carcinoma. Cancer Res. 2020;80(18):3892–3905. doi:10.1158/0008-5472.CAN-19-2691
   PubMed Web of Science ®Google Scholar
• Cheng Y, Li H, Deng Y, et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis. 2018;9(4):422. doi:10.1038/s41419-018-0458-4
   PubMed Web of Science ®Google Scholar
• Cheng JT, Deng YN, Yi HM, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis. 2016;5(2):e198–e198. doi:10.1038/oncsis.2016.7
   PubMedGoogle Scholar
• Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol. 2009;24(6):943–954. doi:10.1111/j.1440-1746.2009.05854.x
   PubMed Web of Science ®Google Scholar
• O’Neill LA, Fitzgerald KA, Bowie AG. The Toll-IL-1 receptor adaptor family grows to five members. Trends Immunol. 2003;24(6):286–290. doi:10.1016/S1471-4906(03)00115-7
   PubMed Web of Science ®Google Scholar
• French SW, Oliva J, French BA, Li J, Bardag-Gorce F. Alcohol, nutrition and liver cancer: role of Toll-like receptor signaling. World J Gastroenterol. 2010;16(11):1344–1348. doi:10.3748/wjg.v16.i11.1344
   PubMed Web of Science ®Google Scholar
• Kairaluoma V, Kemi N, Huhta H, Pohjanen VM, Helminen O. Prognostic role of TLR4 and TLR2 in hepatocellular carcinoma. Acta Oncol. 2021;60(4):554–558. doi:10.1080/0284186X.2021.1877346
   PubMed Web of Science ®Google Scholar
• Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science. 2007;317(5834):121–124. doi:10.1126/science.1140485
   PubMed Web of Science ®Google Scholar
• Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21(4):504–516. doi:10.1016/j.ccr.2012.02.007
   PubMed Web of Science ®Google Scholar
• Jing YY, Han ZP, Sun K, et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012;10:98. doi:10.1186/1741-7015-10-98
   PubMed Web of Science ®Google Scholar
• Tsukamoto H, Mishra L, Alcohol MK. TLR4-TGF-β antagonism, and liver cancer. Hepatol Int. 2014;8(Suppl 2):408–412. doi:10.1007/s12072-013-9489-1
   PubMed Web of Science ®Google Scholar
• Uthaya Kumar DB, Chen CL, Liu JC, et al. TLR4 signaling via NANOG cooperates with stat3 to activate twist1 and promote formation of tumor-initiating stem-like cells in livers of mice. Gastroenterology. 2016;150(3):707–719. doi:10.1053/j.gastro.2015.11.002
   PubMed Web of Science ®Google Scholar
• Zheng Q, Xu J, Lin Z, et al. Inflammatory factor receptor Toll-like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell. J Cell Mol Med. 2018;22(6):3246–3258. doi:10.1111/jcmm.13606
   PubMed Web of Science ®Google Scholar
• Huang Y, Cai B, Xu M, et al. Gene silencing of Toll-like receptor 2 inhibits proliferation of human liver cancer cells and secretion of inflammatory cytokines. PLoS One. 2012;7:7.
   Web of Science ®Google Scholar
• Zhe Y, Li Y, Liu D, Su DM, Liu JG, Li HY. Extracellular HSP70-peptide complexes promote the proliferation of hepatocellular carcinoma cells via TLR2/4/JNK1/2MAPK pathway. Tumour Biol. 2016;37(10):13951–13959. doi:10.1007/s13277-016-5189-5
   PubMedGoogle Scholar
• Tohme S, Yazdani HO, Liu Y, et al. Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction. Hepatology. 2017;66(1):182–197. doi:10.1002/hep.29184
   PubMed Web of Science ®Google Scholar
• Kairaluoma V, Kemi N, Huhta H, Pohjanen VM, Helminen O. Toll-like receptor 5 and 8 in hepatocellular carcinoma. Apmis. 2021;129(8):470–479. doi:10.1111/apm.13142
   PubMed Web of Science ®Google Scholar
• Omaru N, Watanabe T, Kamata K, Minaga K, Kudo M. Activation of NOD1 and NOD2 in the development of liver injury and cancer. Front Immunol. 2022;13:1004439. doi:10.3389/fimmu.2022.1004439
   PubMed Web of Science ®Google Scholar
• Guidotti LG, Inverso D, Sironi L, et al. Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell. 2015;161(3):486–500. doi:10.1016/j.cell.2015.03.005
   PubMed Web of Science ®Google Scholar
• Shalapour S, Lin XJ, Bastian IN, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 2017;551(7680):340–345. doi:10.1038/nature24302
   PubMed Web of Science ®Google Scholar
• Ma J, Zheng B, Goswami S, et al. PD1(Hi) CD8(+) T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma. J Immunother Cancer. 2019;7(1):331. doi:10.1186/s40425-019-0814-7
   PubMed Web of Science ®Google Scholar
• Hsu CL, Ou DL, Bai LY, et al. Exploring markers of exhausted CD8 T cells to predict response to immune checkpoint inhibitor therapy for hepatocellular carcinoma. Liver Cancer. 2021;10(4):346–359. doi:10.1159/000515305
   PubMed Web of Science ®Google Scholar
• McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37:457–495. doi:10.1146/annurev-immunol-041015-055318
   PubMed Web of Science ®Google Scholar
• Haybaeck J, Zeller N, Wolf MJ, et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 2009;16(4):295–308. doi:10.1016/j.ccr.2009.08.021
   PubMed Web of Science ®Google Scholar
• Finkin S, Yuan D, Stein I, et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol. 2015;16(12):1235–1244. doi:10.1038/ni.3290
   PubMed Web of Science ®Google Scholar
• Ma C, Kesarwala AH, Eggert T, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531(7593):253–257. doi:10.1038/nature16969
   PubMed Web of Science ®Google Scholar
• Fu J, Zhang Z, Zhou L, et al. Impairment of CD4+ cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma. Hepatology. 2013;58(1):139–149. doi:10.1002/hep.26054
   PubMed Web of Science ®Google Scholar
• Jia Y, Zeng Z, Li Y, et al. Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression. PLoS One. 2015;10:2.
   Web of Science ®Google Scholar
• Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206(7):1457–1464. doi:10.1084/jem.20090207
   PubMed Web of Science ®Google Scholar
• Garnelo M, Tan A, Her Z, et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut. 2017;66(2):342–351. doi:10.1136/gutjnl-2015-310814
   PubMed Web of Science ®Google Scholar
• Schneider C, Teufel A, Yevsa T, et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut. 2012;61(12):1733–1743. doi:10.1136/gutjnl-2011-301116
   PubMed Web of Science ®Google Scholar
• Miyake T, Abe M, Tokumoto Y, et al. B cell-activating factor is associated with the histological severity of nonalcoholic fatty liver disease. Hepatol Int. 2013;7(2):539–547. doi:10.1007/s12072-012-9345-8
   PubMed Web of Science ®Google Scholar
• von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005;6(4):338–344. doi:10.1038/ni1180
   PubMed Web of Science ®Google Scholar
• Gondek DC, Lu LF, Quezada SA, Sakaguchi S, Noelle RJ. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol. 2005;174(4):1783–1786. doi:10.4049/jimmunol.174.4.1783
   PubMed Web of Science ®Google Scholar
• Sprinzl MF, Galle PR. Immune control in hepatocellular carcinoma development and progression: role of stromal cells. Semin Liver Dis. 2014;34(4):376–388. doi:10.1055/s-0034-1394138
   PubMed Web of Science ®Google Scholar
• Li W, Han J, Wu H. Regulatory T-cells promote hepatitis B virus infection and hepatocellular carcinoma progression. Chronic Dis Transl Med. 2016;2(2):67–80. doi:10.1016/j.cdtm.2016.09.001
   PubMedGoogle Scholar
• Fu J, Xu D, Liu Z, et al. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology. 2007;132(7):2328–2339. doi:10.1053/j.gastro.2007.03.102
   PubMed Web of Science ®Google Scholar
• Wang H, Zhang H, Wang Y, et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J Hepatol. 2021;75(6):1271–1283. doi:10.1016/j.jhep.2021.07.032
   PubMed Web of Science ®Google Scholar
• Mazzoni A, Bronte V, Visintin A, et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol. 2002;168(2):689–695. doi:10.4049/jimmunol.168.2.689
   PubMed Web of Science ®Google Scholar
• Zea AH, Rodriguez PC, Atkins MB, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005;65(8):3044–3048. doi:10.1158/0008-5472.CAN-04-4505
   PubMed Web of Science ®Google Scholar
• Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res. 2010;70(1):68–77. doi:10.1158/0008-5472.CAN-09-2587
   PubMed Web of Science ®Google Scholar
• Wan S, Kuo N, Kryczek I, Zou W, Welling TH. Myeloid cells in hepatocellular carcinoma. Hepatology. 2015;62(4):1304–1312. doi:10.1002/hep.27867
   PubMed Web of Science ®Google Scholar
• Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013;73(8):2435–2444. doi:10.1158/0008-5472.CAN-12-3381
   PubMed Web of Science ®Google Scholar
• Nagai N, Kudo Y, Aki D, Nakagawa H, Taniguchi K. Immunomodulation by inflammation during liver and gastrointestinal tumorigenesis and aging. Int J Mol Sci. 2021;22(5):2238. doi:10.3390/ijms22052238
   PubMed Web of Science ®Google Scholar
• Brittenden J, Heys SD, Ross J, Eremin O. Natural killer cells and cancer. Cancer. 1996;77(7):1226–1243. doi:10.1002/(SICI)1097-0142(19960401)77:7<1226::AID-CNCR2>3.0.CO;2-G
   PubMed Web of Science ®Google Scholar
• Colegio OR, Chu NQ, Szabo AL, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513(7519):559–563.
   PubMed Web of Science ®Google Scholar
• Tahmasebi Birgani M, Carloni V. Tumor microenvironment, a paradigm in hepatocellular carcinoma progression and therapy. Int J Mol Sci. 2017;18(2):405. doi:10.3390/ijms18020405
   PubMed Web of Science ®Google Scholar
• Barry AE, Baldeosingh R, Lamm R, et al. Hepatic stellate cells and hepatocarcinogenesis. Front Cell Dev Biol. 2020;8:709. doi:10.3389/fcell.2020.00709
   PubMed Web of Science ®Google Scholar
• Lee UE, Friedman SL. Mechanisms of hepatic fibrogenesis. Best Pract Res Clin Gastroenterol. 2011;25(2):195–206. doi:10.1016/j.bpg.2011.02.005
   PubMed Web of Science ®Google Scholar
• Zhao W, Zhang L, Yin Z, et al. Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice. Int J Cancer. 2011;129(11):2651–2661. doi:10.1002/ijc.25920
   PubMed Web of Science ®Google Scholar
• Höchst B, Schildberg FA, Sauerborn P, et al. Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J Hepatol. 2013;59(3):528–535. doi:10.1016/j.jhep.2013.04.033
   PubMed Web of Science ®Google Scholar
• Ji J, Eggert T, Budhu A, et al. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology. 2015;62(2):481–495. doi:10.1002/hep.27822
   PubMed Web of Science ®Google Scholar
• Yu MC, Chen CH, Liang X, et al. Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology. 2004;40(6):1312–1321. doi:10.1002/hep.20488
   PubMed Web of Science ®Google Scholar