DOI QR코드

DOI QR Code

Tumor Immune Microenvironment as a New Therapeutic Target for Hepatocellular Carcinoma Development

  • Eunjeong Kim (BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University)
  • 투고 : 2023.09.11
  • 심사 : 2023.11.18
  • 발행 : 2023.12.31

초록

Development of hepatocellular carcinoma (HCC) is driven by a multistep and long-term process. Because current therapeutic strategies are limited for HCC patients, there are increasing demands for understanding of immunotherapy, which has made technological and conceptual innovations in the treatment of cancer. Here, I discuss HCC immunotherapy in the view of interaction between liver resident cells and immune cells.

키워드

과제정보

This research was supported by Kyungpook National University Research Fund, 2022.

참고문헌

  1. Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI (2001) Increased production of immature myeloid cells in cancer patients: A mechanism of immunosuppression in cancer. J Immunol 166:678-689.  https://doi.org/10.4049/jimmunol.166.1.678
  2. Bandyopadhyay K, Marrero I, Kumar V (2016) NKT cell subsets as key participants in liver physiology and pathology. Cell Mol Immunol 13:337-346.  https://doi.org/10.1038/cmi.2015.115
  3. Benetti A, Berenzi A, Gambarotti M, Garrafa E, Gelati M, Dessy E, Portolani N, Piardi T, Giulini SM, Caruso A, Invernici G, Parati EA, Nicosia R, Alessandri G (2008) Transforming growth factor-β1 and CD105 promote the migration of hepatocellular carcinoma-derived endothelium. Cancer Res 68:8626-8634.  https://doi.org/10.1158/0008-5472.CAN-08-1218
  4. Bu L, Baba H, Yoshida N, Miyake K, Yasuda T, Uchihara T, Tan P, Ishimoto T (2019) Biological heterogeneity and versatility of cancer-associated fibroblasts in the tumor microenvironment. Oncogene 38:4887-4901.  https://doi.org/10.1038/s41388-019-0765-y
  5. Chen MM, Xiao X, Lao XM, Wei Y, Liu RX, Zeng QH, Wang JC, Ouyang FZ, Chen DP, Chan KW, Shi DC, Zheng L, Kuang DM (2016) Polarization of tissue-resident TFH-like cells in human hepatoma bridges innate monocyte inflammation and M2b macrophage polarization. Cancer Discov 6:1182-1195.  https://doi.org/10.1158/2159-8290.CD-16-0329
  6. Deng Y, Cheng J, Fu B, Liu W, Chen G, Zhang Q, Yang Y (2017) Hepatic carcinoma-associated fibroblasts enhance immune suppression by facilitating the generation of myeloid-derived suppressor cells. Oncogene 36:1090-1101.  https://doi.org/10.1038/onc.2016.273
  7. Dudley AC (2012) Tumor endothelial cells. Cold Spring Harb Perspect Med 2:a006536. 
  8. El-Serag HB (2011) Hepatocellular carcinoma. N Engl J Med 365:1118-1127.  https://doi.org/10.1056/NEJMra1001683
  9. El-Serag HB, Lenhard Rudolph K (2007) Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 132:2557-2576.  https://doi.org/10.1053/j.gastro.2007.04.061
  10. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, Scott Worthen G, Albelda SM (2009) Polarization of tumor-associated neutrophil phenotype by TGF-β: "N1" versus "N2" TAN. Cancer Cell 16:183-194.  https://doi.org/10.1016/j.ccr.2009.06.017
  11. Friedman SL (2008) Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88:125-172.  https://doi.org/10.1152/physrev.00013.2007
  12. Fu J, Xu D, Liu Z, Shi M, Zhao P, Fu B, Zhang Z, Yang H, Zhang H, Zhou C, Yao J, Jin L, Wang H, Yang Y, Fu YX, Wang FS (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328-2339.  https://doi.org/10.1053/j.gastro.2007.03.102
  13. Fu Y, Liu S, Zeng S, Shen H (2019) From bench to bed: The tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res 38:396. 
  14. Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586-2593.  https://doi.org/10.1200/JCO.2006.09.4565
  15. Garnelo M, Tan A, Her Z, Yeong J, Lim CJ, Chen J, Lim KH, Weber A, Chow P, Chung A, Ooi LLPJ, Toh HC, Heikenwalder M, Ng IO, Nardin A, Chen Q, Abastado JP, Chew V (2017) Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66:342-351.  https://doi.org/10.1136/gutjnl-2015-310814
  16. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50:799-807.  https://doi.org/10.1002/hep.23054
  17. Hou J, Zhang H, Sun B, Karin M (2020) The immunobiology of hepatocellular carcinoma in humans and mice: Basic concepts and therapeutic implications. J Hepatol 72:167-182.  https://doi.org/10.1016/j.jhep.2019.08.014
  18. Hu CE, Gan J, Zhang RD, Cheng YR, Huang GJ (2011) Up-regulated myeloid-derived suppressor cell contributes to hepatocellular carcinoma development by impairing dendritic cell function. Scand J Gastroenterol 46:156-164.  https://doi.org/10.3109/00365521.2010.516450
  19. Huang Y, Ge W, Zhou J, Gao B, Qian X, Wang W (2021) The role of tumor associated macrophages in hepatocellular carcinoma. J Cancer 12:1284-1294.  https://doi.org/10.7150/jca.51346
  20. Jiang R, Tan Z, Deng L, Chen Y, Xia Y, Gao Y, Wang X, Sun B (2011) Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 54:900-909.  https://doi.org/10.1002/hep.24486
  21. Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y (2013) 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 73:2435-2444. 
  22. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, Hohmeyer A, Gereke M, Rudalska R, Potapova A, Iken M, Vucur M, Weiss S, Heikenwalder M, Khan S, Gil J, Bruder D, Manns M, Schirmacher P, Tacke F, Ott M, Luedde T, Longerich T, Kubicka S, Zender L (2011) Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547-551.  https://doi.org/10.1038/nature10599
  23. Khomich O, Ivanov AV, Bartosch B (2019) Metabolic hallmarks of hepatic stellate cells in liver fibrosis. Cells 9:24. 
  24. Kitamura T, Qian BZ, Pollard JW (2015) Immune cell promotion of metastasis. Nat Rev Immunol 15:73-86.  https://doi.org/10.1038/nri3789
  25. Kumar V, Patel S, Tcyganov E, Gabrilovich DI (2016) The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol 37:208-220.  https://doi.org/10.1016/j.it.2016.01.004
  26. Leliefeld PHC, Koenderman L, Pillay J (2015) How neutrophils shape adaptive immune responses. Front Immunol 6:471. 
  27. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378-390.  https://doi.org/10.1056/NEJMoa0708857
  28. Lu C, Rong D, Zhang B, Zheng W, Wang X, Chen Z, Tang W (2019) Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: Challenges and opportunities. Mol Cancer 18:130. 
  29. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, Fuchs JR, Eubank TD, Frankel WL, Bekaii-Saab T, Bloomston M, Lesinski GB (2013) Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res 73:3007-3018. 
  30. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436-444.  https://doi.org/10.1038/nature07205
  31. McPherson S, Henderson E, Burt AD, Day CP, Anstee QM (2014) Serum immunoglobulin levels predict fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 60:1055-1062.  https://doi.org/10.1016/j.jhep.2014.01.010
  32. Mougiakakos D, Choudhury A, Lladser A, Kiessling R, Christian Johansson C (2010) Chapter 3 - Regulatory T cells in cancer. Adv Cancer Res 107:57-117.  https://doi.org/10.1016/S0065-230X(10)07003-X
  33. Murdoch C, Giannoudis A, Lewis CE (2004) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104:2224-2234.  https://doi.org/10.1182/blood-2004-03-1109
  34. Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8:618-631.  https://doi.org/10.1038/nrc2444
  35. Ormandy LA, Farber A, Cantz T, Petrykowska S, Wedemeyer H, Horning M, Lehner F, Manns MP, Korangy F, Greten TF (2006) Direct ex vivo analysis of dendritic cells in patients with hepatocellular carcinoma. World J Gastroenterol 12:3275-3282.  https://doi.org/10.3748/wjg.v12.i20.3275
  36. Ormandy LA, Hillemann T, Wedemyer H, Manns MP, Greten TF, Korangy F (2005) Increased populations of regulatory T cells in peripheral blood of patients with hepatocellular carcinoma. Cancer Res 65:2457-2464.  https://doi.org/10.1158/0008-5472.CAN-04-3232
  37. Pham L, Kyritsi K, Zhou T, Ceci L, Baiocchi L, Kennedy L, Chakraborty S, Glaser S, Francis H, Alpini G, Sato K (2022) The functional roles of immune cells in primary liver cancer. Am J Pathol 192:826-836. 
  38. Rombouts K, Carloni V (2013) The fibrotic microenvironment as a heterogeneity facet of hepatocellular carcinoma. Fibrogenesis Tissue Repair 6:17. 
  39. Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, Vrbanac AF, Li W, Perkins A, Matsutani T, Zhong Z, Dhar D, Navas-Molina JA, Xu J, Loomba R, Downes M, Yu RT, Evans RM, Dorrestein PC, Knight R, Benner C, Anstee QM, Karin M (2017) Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551:340-345.  https://doi.org/10.1038/nature24302
  40. Tan H, Wang S, Zhao L (2017) A tumour-promoting role of Th9 cells in hepatocellular carcinoma through CCL20 and STAT3 pathways. Clin Exp Pharmacol Physiol 44:213-221.  https://doi.org/10.1111/1440-1681.12689
  41. Teng CF, Wang T, Wu TH, Lin JH, Shih FY, Shyu WC, Jeng LB (2020) Combination therapy with dendritic cell vaccine and programmed death ligand 1 immune checkpoint inhibitor for hepatocellular carcinoma in an orthotopic mouse model. Ther Adv Med Oncol 12:1758835920922034. 
  42. Togashi Y, Shitara K, Nishikawa H (2019) Regulatory T cells in cancer immunosuppression - Implications for anticancer therapy. Nat Rev Clin Oncol 16:356-371.  https://doi.org/10.1038/s41571-019-0175-7
  43. Villanueva A (2019) Hepatocellular carcinoma. N Engl J Med 380:1450-1462.  https://doi.org/10.1056/NEJMra1713263
  44. Worns MA, Galle PR (2017) Immune oncology in hepatocellular carcinoma-Hype and hope. Lancet 389:2448-2449.  https://doi.org/10.1016/S0140-6736(17)31044-9
  45. Wu K, Kryczek I, Chen L, Zou W, Welling TH (2009) 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.  https://doi.org/10.1158/0008-5472.CAN-09-0901
  46. Yang JD, Nakamura I, Roberts LR (2011) The tumor microenvironment in hepatocellular carcinoma: Current status and therapeutic targets. Semin Cancer Biol 21:35-43.  https://doi.org/10.1016/j.semcancer.2010.10.007
  47. Yang XH, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H, Sato Y, Abo T, Horwitz DA, Aoyagi Y (2006) Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol 45:254-262.  https://doi.org/10.1016/j.jhep.2006.01.036
  48. Yang Z, Zhang B, Li D, Lv M, Huang C, Shen GX, Huang B (2010) Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One 5:e8922. 
  49. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, Wu C, Li SP, Zheng L (2009) Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. J Hepatol 50:980-989.  https://doi.org/10.1016/j.jhep.2008.12.033
  50. Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, Fan J, Cao Y, Dai Z, Zhou J (2016) Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 150:1646-1658.E17.  https://doi.org/10.1053/j.gastro.2016.02.040
  51. Zhu S, Zhang H, Bai L (2018) NKT cells in liver diseases. Front Med 12:249-261. https://doi.org/10.1007/s11684-018-0622-3
  52. Ziani L, Chouaib S, Thiery J (2018) Alteration of the antitumor immune response by cancer-associated fibroblasts. Front Immunol 9:414.