Роль цитокинов при гепатоцеллюлярной карциноме

Рак печени занимает пятое место в мире среди всех видов рака и третье место среди смертей, связанных с раковыми заболеваниями. Гепатоцеллюлярная карцинома (ГЦК) является первичной, не включающей метастазы в печень из других участков и самой распространенной формой рака печени и одной из ведущей причиной смерти от рака во всем мире. ГЦК включает генетически и морфологически гетерогенную группу злокачественных опухолей. ГЦК характеризуется гендерной предрасположенностью: она встречается у мужчин в 1,5 чаще, чем у женщин. Вирусные инфекции, такие как гепатит В и С, являются основными факторами риска развития ГЦК, но также в развитых странах неалкогольный стеатогепатит (НАСГ), связанный с метаболическим синдромом и сахарным диабетом второго типа, становится все более часто встречаемым фактором риска развития заболевания. Механизмы, лежащие в основе развития ГЦК, основываются на генетических изменениях опухолевых клеток и их микроокружения. В последнее время роль изменений в микроокружении опухоли привлекает большее внимание и становится ключевой характеристикой в патогенезе ГЦК на всех стадиях злокачественного процесса. Гепатоциты имеют тесную связь с иммунными клетками, так как в печени помимо гепатоцитов присутствуют клетки Купфера, клетки миелоидного ряда (дендритные клетки, моноциты и нейтрофилы) и другие типы клеток (Т- и В-лимфоциты, NK и NKT и т. д.). Выделяемые различными иммунными клетками печени цитокины оказывают влияние на процессы в печени, такие как развитие воспаления и рака. Хроническое воспаление возникает в результате постоянных стимулов или недостатков в механизмах разрешения воспаления. Его ключевые особенности включают инфильтрацию иммунных клеток, наличие медиаторов воспаления и дисбаланс про- и противовоспалительных цитокинов, приводящих к возникновению агрессивного ангиогенеза и ремоделирования тканей, что в свою очередь приводит к озлокачествлению процесса. На данный момент существуют несколько подходов в лечении ГЦК в зависимости от стадии заболевания. Иммунотерапия и ее комбинации показали положительную динамику, и дальнейшие исследования в этой области помогут в борьбе на терминальных стадиях ГЦК. Разнообразные цитокины и их функции в развитии ГЦК являются предметом настоящего обзора.

1. Агеева Л.И., Александрова Г.А., Зайченко Н.М., Кириллова Г.Н., Леонов С.А., Огрызко Е.В., Титова И.А., Харькова Т.Л., Чумарина В.Ж., Пак Ден Нам. Здравоохранение в России. 2019: Стат.сб. / Росстат. М., 2019. 170 с.

2. Карин А.Д., Старинский В.В., Петрова Г.В. Злокачественные новообразования в России в 2018 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2019. 250 с.

3. Aleksandrova K., Boeing H., Nöthlings U., Jenab M., Fedirko V., Kaaks R., Lukanova A., Trichopoulou A., Trichopoulos D., Boffetta P., Trepo E., Westhpal S., Duarte-Salles T., Stepien M., Overvad K., Tjønneland A., Halkjaer J., Boutron-Ruault M.-C., Dossus L., Racine A., Lagiou P., Bamia C., Benetou V., Agnoli C., Palli D., Panico S., Tumino R., Vineis P., Bueno-de-Mesquita B., Peeters P.H., Gram I.T., Lund E., Weiderpass E., Quirós J.R., Agudo A., Sánchez M.-J., Gavrila D., Barricarte A., Dorronsoro M., Ohlsson B., Lindkvist B., Johansson A., Sund M., Khaw K.-T., Wareham N., Travis R.C., Riboli E., Pischon T. Inflammatory and metabolic biomarkers and risk of liver and biliary tract cancer. Hepatology, 2014, Vol. 60, no. 3, pp. 858-871.

4. Andrews K.J., Ribas A., Butterfield L.H., Vollmer C.M., Eilber F.C., Dissette V.B., Nelson S.D., Shintaku P., Mekhoubad S., Nakayama T., Taniguchi M., Glaspy J.A., McBride W.H., Economou J.S. Adenovirus-interleukin-12-mediated tumor regression in a murine hepatocellular carcinoma model is not dependent on CD1-restricted natural killer T cells. Cancer Res., 2000, Vol. 60, no. 22, pp. 6457-6464.

5. Anstee Q.M., Reeves H.L., Kotsiliti E., Govaere O., Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol., 2019, Vol. 16, no. 7, pp. 411-428.

6. Attallah A.M., El-Far M., Zahran F., Shiha G.E., Farid K., Omran M.M., Abdelrazek M.A., Attallah A.A., el-Beh A.A., El-Hosiny R.M., El-Waseef A.M. Interferon-gamma is associated with hepatic dysfunction in fibrosis, cirrhosis, and hepatocellular carcinoma. J. Immunoassay Immunochem., 2016, Vol. 37, no. 6, pp. 597-610.

7. Balkwill F. Tumor necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev., 2002, Vol. 13, no. 2, pp. 135-141.

8. Balkwill F. Tumour necrosis factor and cancer. Nat. Rev. Cancer., 2009, Vol. 9, no. 5, pp. 361-371.

9. Beckebaum S., Zhang X., Chen X., Yu Z., Frilling A., Dworacki G., Grosse-Wilde H., Broelsch C.E., Gerken G., Cicinnati V.R. Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin. Cancer Res., 2004, Vol. 10, no. 21, pp. 7260-7269.

10. Bergmann J., Müller M., Baumann N., Reichert M., Heneweer C., Bolik J., Lücke K., Gruber S., Carambia A., Boretius S., Leuschner I., Becker T., Rabe B., Herkel J., Wunderlich F.T., Mittrücker H.-W., Rose-John S., Schmidt-Arras D. IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice. Hepatology, 2017, Vol. 65, no. 1, pp. 89-103.

11. Billiau A. Interferon-gamma: biology and role in pathogenesis. Adv. Immunol., 1996, Vol. 62, pp. 61-130.

12. Blouin C.M., Hamon Y., Gonnord P., Boularan C., Kagan J., de Lesegno C.V., Ruez R., Mailfert S., Bertaux N., Loew D., Wunder C., Johannes L., Vogt G., Contreras F.-X., Marguet D., Casanova J.-L., Galès C., He H.-T., Lamaze C. Glycosylation-dependent IFN-γR partitioning in lipid and actin nanodomains is critical for JAK activation. Cell, 2016, Vol. 166, no. 4, pp. 920-934.

13. Boraschi D., Tagliabue A. The interleukin-1 receptor family. Semin. Immunol., 2013, Vol. 25, no. 6, pp. 394-407.

14. Bortolami M., Venturi C., Giacomelli L., Scalerta R., Bacchetti S., Marino F., Floreani A., Lise M., Naccarato R., Farinati F. Cytokine, infiltrating macrophage and T cell-mediated response to development of primary and secondary human liver cancer. Dig. Liver Dis., 2002, Vol. 34, no. 11, pp. 794-801.

15. Cabillic F., Corlu A. Regulation of transdifferentiation and retrodifferentiation by inflammatory cytokines in hepatocellular carcinoma. Gastroenterology, 2016, Vol. 151, no. 4, pp. 607-615.

16. Chan S.L., Wong V.W., Qin S., Chan H.L. Infection and cancer: the case of hepatitis B. J. Clin. Oncol., 2016, Vol. 34, no. 1, pp. 83-90.

17. Chau G.Y., Wu C.W., Lui W.Y., Chang T.J., Kao H.L., Wu L.H., King K.L., Loong C.C., Hsia C.Y., Chi C.W. Serum interleukin-10 but not interleukin-6 is related to clinical outcome in patients with resectable hepatocellular carcinoma. Ann. Surg., 2000, Vol. 231, no. 4, pp. 552-558.

18. Dasgupta P., Henshaw C., Youlden D.R., Clark P.J., Aitken J.F., Baade P.D. Global trends in incidence rates of primary adult liver cancers: a systematic review and meta-analysis. Front. Oncol., 2020, Vol. 10, 171. doi: 10.3389/fonc.2020.00171.

19. Estes C., Razavi H., Loomba R., Younossi Z., Sanyal A.J. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology, 2018, Vol. 67, no. 1, pp. 123-133.

20. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol., 2018, Vol. 69, no. 1, pp. 182-236.

21. Ferrín G., Guerrero M., Amado V., Rodríguez-Perálvarez M., de la Mata M. Activation of mTOR signaling pathway in hepatocellular carcinoma. Int. J. Mol. Sci., 2020, Vol. 21, no. 4, 1266. doi: 10.3390/ijms21041266.

22. Fu Y., Liu S., Zeng S., Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J. Exp. Clin. Cancer Res., 2019, Vol. 38, no. 1, 396. doi: 10.1186/s13046-019-1396-4.

23. Fung A.S., Tam V.C., Meyers D.E., Sim H.-W., Knox J.J., Zaborska V., Davies J., Ko Y.-J., Batuyong E., Samawi H., Cheung W.Y., Lee-Ying R. Second-line treatment of hepatocellular carcinoma after sorafenib: Characterizing treatments used over the past 10 years and real-world eligibility for cabozantinib, regorafenib, and ramucirumab. Cancer Med., 2020, Vol. 9, no. 13, pp. 4640-4647.

24. Hatting M., Spannbauer M., Peng J., Masaoudi M.A., Sellge G., Nevzorova Y.A., Gassler N., Liedtke C., Cubero F.J., Trautwein C. Lack of gp130 expression in hepatocytes attenuates tumor progression in the DEN model. Cell Death Dis., 2015, Vol. 6, no. 3, e1667. doi: 10.1038/cddis.2014.590.

25. He G., Dhar D., Nakagawa H., Font-Burgada J., Ogata H., Jiang Y., Shalapour S., Seki E., Yost S.E., Jepsen K., Frazer K.A., Harismendy O., Hatziapostolou M., Iliopoulos D., Suetsugu A., Hoffman R.M., Tateishi R., Koike K., Karin M. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell, 2013, Vol. 155, no. 2, pp. 384-396.

26. He G., Yu G.Y., Temkin V., Ogata H., Kuntzen C., Sakurai T., Sieghart W., Peck-Radosavljevic M., Leffert H.L., Karin M. Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell, 2010, Vol. 17, no. 3, pp. 286-297.

27. Hotamisligil G.S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell, 2010, Vol. 140, no. 6, pp. 900-917.

28. Jemal A., Ward E.M., Johnson C.J., Cronin K.A., Ma J., Ryerson B., Mariotto A., Lake A.J., Wilson R., Sherman R.L., Anderson R.N., Henley S.J., Kohler B.A., Penberthy L., Feuer E.J., Weir H.K. Annual report to the nation on the status of cancer, 1975-2014, Featuring Survival. J. Natl Cancer Inst., 2017, Vol. 109, no. 9. djx030. doi: 10.1093/jnci/djx030.

29. Kelley R.K., Gane E., Assenat E., Siebler J., Galle P.R., Merle P., Hourmand I.O., Cleverly A., Zhao Y., Gueorguieva I., Lahn M., Faivre S., Benhadji K.A., Giannelli G. A phase 2 study of galunisertib (TGF-β1 Receptor Type I Inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin. Transl. Gastroenterol., 2019, Vol. 10, no. 7. e00056. doi: 10.14309/ctg.0000000000000056.

30. Kishimoto T. IL-6: from its discovery to clinical applications. Int. Immunol., 2010, Vol. 22, no. 5, pp. 347-352.

31. Kohla M.A.S., Attia A., Darwesh N., Obada M., Taha H., Youssef M.F. Association of serum levels of transforming growth factor β1 with disease severity in patients with hepatocellular carcinoma. Hepatoma Res., 2017, Vol. 3, pp. 294-301.

32. Komita H., Homma S., Saotome H., Zeniya M., Ohno T., Toda G. Interferon-gamma produced by interleukin-12-activated tumor infiltrating CD8+ T cells directly induces apoptosis of mouse hepatocellular carcinoma. J. Hepatol., 2006, Vol. 45, no. 5, pp. 662-672.

33. Krelin Y., Voronov E., Dotan S., Elkabets M., Reich E., Fogel M., Huszar M., Iwakura Y., Segal S., Dinarello C.A., Apte R.N. Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res., 2007, Vol. 67, no. 3, pp. 1062-1071.

34. Kumari N., Dwarakanath B.S., Das A., Bhatt A.N. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol., 2016, Vol. 37, no. 9, pp. 11553-11572.

35. Lanton T., Shriki A., Nechemia-Arbely Y., Abramovitch R., Levkovitch O., Adar R., Rosenberg N., Paldor M., Goldenberg D., Sonnenblick A., Peled A., Rose-John S., Galun E., Axelrod J.H. Interleukin 6-dependent genomic instability heralds accelerated carcinogenesis following liver regeneration on a background of chronic hepatitis. Hepatology, 2017, Vol. 65, no. 5, pp. 1600-1611.

36. Lasek W., Zagożdżon R., Jakobisiak M. Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother., 2014, Vol. 63, no. 5, pp. 419-435.

37. Lee I.C., Huang Y.H., Chau G.Y., Huo T.I., Su C.W., Wu J.C., Lin H.C.. Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments. Int. J. Cancer., 2013, Vol. 133, no. 12, pp. 2895-2902.

38. Lee J.H., Lee J.H., Lim Y.S., Yeon J.E., Song T.-J., Yu S.J., Gwak G.-Y., Kim K.M., Kim Y.J., Lee J.W., Yoon J.-H. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology, 2015, Vol. 148, no. 7, pp. 1383-1391.

39. Li J., Zeng M., Yan K., Yang Y., Li H., Xu X.. IL-17 promotes hepatocellular carcinoma through inhibiting apoptosis induced by IFN-γ. Biochem. Biophys. Res. Commun., 2020, Vol. 522, no. 2, pp. 525-531.

40. Lin W.W., Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest., 2007, Vol. 117, no. 5, pp. 1175-1183.

41. Liu Z., Liu X., Liang J., Liu Y., Hou X., Zhang M., Li Y., Jiang X. Immunotherapy for hepatocellular carcinoma: current status and future prospects. Front. Immunol., 2021, Vol. 12, 765101. doi: 10.3389/fimmu.2021.765101.

42. Llovet J.M., Ricci S., Mazzaferro V., Hilgard P., Gane E., Blanc J.-F., de Oliveira A.C., Santoro A., Raoul J.-L., Forner A., Schwartz M., Porta C., Zeuzem S., Bolondi L., Greten T.F., Galle P.R., Seitz J.-F., Borbath I., Häussinger D., Giannaris T., Shan M., Moscovici M., Voliotis D., Bruix J., SHARP Investigators Study Group Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, Vol. 359, no. 4, pp. 378-390.

43. Lo C.H., Chang C.M., Tang S.W., Pan W.-Y., Fang C.-C., Chen Y., Wu P.-Y., Chen K.-Y., Ma H.-I., Xiao X., Tao M.-H. Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma. J. Gene Med., 2010, Vol. 12, no. 5, pp. 423-434.

44. Ma Y., Xu Y.C., Tang L., Zhang Z., Wang J., Wang H.X. Cytokine-induced killer (CIK) cell therapy for patients with hepatocellular carcinoma: efficacy and safety. Exp. Hematol. Oncol., 2012, Vol. 1, no. 1, 11. doi: 10.1186/2162-3619-1-11.

45. Macarthur M., Hold G.L., El-Omar E.M. Inflammation and Cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy. Am. J. Physiol. Gastrointest. Liver Physiol., 2004, Vol. 286, no. 4, G515-20. doi: 10.1152/ajpgi.00475.2003.

46. Machado M.V., Diehl A.M. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology, 2016, Vol. 150, no. 8, pp. 1769-1777.

47. Marrero J.A., Kulik L.M., Sirlin C.B., Zhu A.X., Finn R.S., Abecassis M.M., Roberts L.R., Heimbach J.K. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the american association for the study of liver diseases. Hepatology, 2018, Vol. 68, no. 2, pp. 723-750.

48. Massagué J, Gomis RR. The logic of TGFbeta signaling. FEBS Lett., 2006, Vol. 580, no. 12, pp. 2811-2820.

49. Mazzaferro V., Regalia E., Doci R., Andreola S., Pulvirenti A., Bozzetti F., Montalto F., Ammatuna M., Morabito A., Gennari L. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N. Engl. J. Med., 1996, Vol. 334, no. 11, pp. 693-699.

50. Medzhitov R. Origin and physiological roles of inflammation. Nature, 2008, Vol. 454, no. 7203, pp. 428-435.

51. Migita K., Miyazoe S., Maeda Y., Daikoku M., Abiru S., Ueki T., Yano K., Nagaoka S., Matsumoto T., Nakao K., Hamasaki K., Yatsuhashi H., Ishibashi H., Eguchi K. Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection-association between TGF-beta1 polymorphisms and hepatocellular carcinoma. J. Hepatol., 2005, Vol. 42, no. 4, pp. 505-510.

52. Nakazaki H. Preoperative and postoperative cytokines in patients with cancer. Cancer, 1992, Vol. 70, no. 3, pp. 709-713.

53. Nguyen K.G., Vrabel M.R., Mantooth S.M., Hopkins J.J., Wagner E.S., Gabaldon T.A., Zaharoff D.A. Localized Interleukin-12 for cancer immunotherapy. Front. Immunol., 2020, Vol. 11, 575597. doi: 10.3389/fimmu.2020.575597.

54. Nishida N., Yada N., Hagiwara S., Sakurai T., Kitano M., Kudo M. Unique features associated with hepatic oxidative DNA damage and DNA methylation in non-alcoholic fatty liver disease. J. Gastroenterol. Hepatol., 2016, Vol. 31, no. 9, pp. 1646-1653.

55. Park E.J., Lee J.H., Yu G.Y., He G., Ali S.R., Holzer R.G., Osterreicher C.H., Takahashi H., Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell, 2010, Vol. 140, no. 2, pp. 197-208.

56. Peron J.M., Couderc B., Rochaix P., Douin-Echinard V., Asnacios A., Souque A., Voigt J.-J., Buscail L., Vinel J.-P., Favre G. Treatment of murine hepatocellular carcinoma using genetically modified cells to express interleukin-12. J. Gastroenterol. Hepatol., 2004, Vol. 19, no. 4, pp. 388-396.

57. Pützer B.M., Stiewe T., Rödicker F., Schildgen O., Rühm S., Dirsch O., Fiedler M., Damen U., Tennant B., Scherer C., Graham F.L., Roggendorf M. Large nontransplanted hepatocellular carcinoma in woodchucks: treatment with adenovirus-mediated delivery of interleukin 12/B7.1 genes. J. Natl Cancer Inst., 2001, Vol. 93, no. 6, pp. 472-479.

58. Raoul J.L., Forner A., Bolondi L., Cheung T.T., Kloeckner R., de Baere T. Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence. Cancer Treat. Rev., 2019, Vol. 72, pp. 28-36.

59. Rébé C., Ghiringhelli F. Interleukin-1β and Cancer. Cancers (Basel), 2020, Vol. 12, no. 7, 1791. doi: 10.3390/cancers12071791.

60. Reichner J.S., Mulligan J.A., Spisni R., Sotomayor E.A., Albina J.E., Bland K.I. Effect of IL-6 overexpression on the metastatic potential of rat hepatocellular carcinoma cells. Ann. Surg. Oncol., 1998, Vol. 5, no. 3, pp. 279-286.

61. Riley J.K., Takeda K., Akira S., Schreiber R.D. Interleukin-10 receptor signaling through the JAK-STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J. Biol. Chem., 1999, Vol. 274, no. 23, pp. 16513-16521.

62. Sabat R., Grütz G., Warszawska K., Kirsch S., Witte E., Wolk K., Geginat J. Biology of interleukin-10. Cytokine Growth Factor Rev., 2010, Vol. 21, no. 5, pp. 31-44.

63. Santer F.R., Malinowska K., Culig Z., Cavarretta I.T. Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endoc. Relat. Cancer, 2010, Vol. 17, no. 1, pp. 241-253.

64. Sato T., Terai M., Tamura Y., Alexeev V., Mastrangelo M.J., Selvan S.R. Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy. Immunol. Res., 2011, Vol. 51, no. 2-3, pp. 170-182.

65. Schoenfeld H.J., Poeschl B., Frey J.R., Loetscher H., Hunziker W., Lustig A., Zulauf M. Efficient purification of recombinant human tumor necrosis factor beta from Escherichia coli yields biologically active protein with a trimeric structure that binds to both tumor necrosis factor receptors. J. Biol. Chem., 1991, Vol. 266, no. 6, pp. 3863-3869.

66. Schulze K., Imbeaud S., Letouzé E., Alexandrov L.B., Calderaro J., Rebouissou S., Couchy G., Meiller C., Shinde J., Soysouvanh F., Calatayud A.-L., Pinyol R., Pelletier L., Balabaud C., Laurent A., Blanc J.-F., Mazzaferro V., Calvo F., Villanueva A., Nault J.-C., Bioulac-Sage P., Stratton M.R., Llovet J.M., Zucman-Rossi J. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet., 2015, Vol. 47, no. 5, pp. 505-511.

67. Seehawer M., Heinzmann F., D’Artista L., Harbig J., Roux P.-F., Hoenicke L., Dang H., Klotz S., Robinson L., Doré G., Rozenblum N., Kang T.-W., Chawla R., Buch T., Vucur M., Roth M., Zuber J., Luedde T., Sipos B., Longerich T., Heikenwälder M., Wang X.W., Bischof O., Zender L. Necroptosis microenvironment directs lineage commitment in liver cancer. Nature, 2018, Vol. 564, pp. 69-75.

68. Shakiba E., Ramezani M., Sadeghi M. Evaluation of serum interleukin-10 levels in hepatocellular carcinoma patients: a systematic review and meta-analysis. Clin. Exp. Hepatol., 2018, Vol. 4, no. 1, pp. 35-40.

69. Shanahan J.C., St Clair W. Tumor necrosis factor-alpha blockade: a novel therapy for rheumatic disease. Clin. Immunol., 2002, Vol. 103, pp. 231-242.

70. Shen Y., Wei Y., Wang Z., Jing Y., He H., Yuan J., Li R., Zhao Q., Wei L., Yang T., Lu J. TGF-β regulates hepatocellular carcinoma progression by inducing Treg cell polarization. Cell. Physiol. Biochem., 2015, Vol. 35, no. 4, pp. 1623-1632.

71. Sia D., Villanueva A., Friedman S.L., Llovet J.M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology, 2017, Vol. 152, no. 4, pp. 745-761.

72. Song le H., Binh V.Q., Duy D.N., Kun J.F., Bock T.C., Kremsner P.G., Luty A.J. Serum cytokine profiles associated with clinical presentation in Vietnamese infected with hepatitis B virus. J. Clin. Virol., 2003, Vol. 28, no. 1, pp. 93-103.

73. Szabo G., Petrasek J. Inflammasome activation and function in liver disease. Nat. Rev. Gastroenterol. Hepatol., 2015, Vol. 12, no. 7, pp. 387-400.

74. Tak K.H., Yu G.I., Lee M.Y., Shin D.H. Association between polymorphisms of interleukin 1 family genes and hepatocellular carcinoma. Med. Sci. Monit., 2018, Vol. 24, pp. 3488-3495.

75. Tu S., Bhagat G., Cui G., Takaishi S., Kurt-Jones E.A., Rickman B., Betz K.S., Penz-Oesterreicher M., Bjorkdahl O., Fox J.G., Wang T.C. Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell, 2008, Vol. 14, no. 5, pp. 408-419.

76. Tzartzeva K., Obi J., Rich N.E., Parikh N.D., Marrero J.A., Yopp A., Waljee A.K., Singal A.G. Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis. Gastroenterology, 2018, Vol. 154, no. 6, pp. 1706-1718.

77. Vignali D.A., Kuchroo V.K. IL-12 family cytokines: immunological playmakers. Nat. Immunol., 2012, Vol. 13, no. 8, pp. 722-728.

78. Wang Q., Cheng F., Ma T.T., Xiong H.-Y., Li Z.-W., Xie C.-L., Liu C.-Y., Tu Z.-G. Interleukin-12 inhibits the hepatocellular carcinoma growth by inducing macrophage polarization to the M1-like phenotype through downregulation of Stat-3. Mol. Cell Biochem., 2016, Vol. 415, no. 1-2, pp.157-168.

79. Wang Z., Qiu S.J., Ye S.L., Tang Z.Y., Xiao X. Combined IL-12 and GM-CSF gene therapy for murine hepatocellular carcinoma. Cancer Gene Ther., 2001, Vol. 8, no. 10, pp. 751-758.

80. Watkins S.K., Egilmez N.K., Suttles J., Stout R.D. IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J. Immunol., 2007, Vol. 178, no. 3, pp. 1357-1362.

81. Wheelhouse N.M., Chan Y.S., Gillies S.E., Caldwell H., Ross J.A., Harrison D.J., Prost S. TNF-alpha induced DNA damage in primary murine hepatocytes. Int. J. Mol. Med., 2003, Vol. 12, no. 6, pp. 889-894.

82. Wolin K.Y., Carson K., Colditz G.A. Obesity and cancer. Oncologist, 2010, Vol. 15, no. 6, pp. 556-565.

83. World Health organization, The Global Cancer Observatory, 2020. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf.

84. Xu L., Wang J., Kim Y., Shuang Z.-Y., Zhang Y.-J., Lao X.-M., Li Y.-Q., Chen M.-S., Pawlik T.M., Xia J.-C., Li S.-P., Lau W.-Y. A randomized controlled trial on patients with or without adjuvant autologous cytokine-induced killer cells after curative resection for hepatocellular carcinoma. Oncoimmunology, 2015, Vol. 5, no. 3, e1083671. doi: 10.1080/2162402X.2015.1083671.

85. Yamashita T., Kudo M., Ikeda K., Izumi N., Tateishi R., Ikeda M., Aikata H., Kawaguchi Y., Wada Y., Numata K., Inaba Y., Kuromatsu R., Kobayashi M., Okusaka T., Tamai T., Kitamura C., Saito K., Haruna K., Okita K., Kumada H. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J. Gastroenterol., 2020, Vol. 55, no. 1, pp. 113-122.

86. Yang L., Huang J., Ren X., Gorska A.E., Chytil A., Aakre M., Carbone D.P., Matrisian L.M., Richmond A., Lin P.C., Moses H.L. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1 + CD11b + myeloid cells that promote metastasis. Cancer Cell, 2008, Vol. 13, no. 1, pp. 23-35.

87. Yu L.X., Ling Y., Wang H.Y. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis. Oncol, 2018, Vol. 2, no. 1, 6. doi: 10.1038/s41698-018-0048-z.

88. Zekri A.-R.N., El Deeb S., Bahnassy A.A., Badr A.M., Abdellateif M.S., Esmat G., Salama H., Mohanad M., el-Dien A.E., Rabah S., Elkader A.A. Role of relevant immune-modulators and cytokines in hepatocellular carcinoma and premalignant hepatic lesions. World J. Gastroenterol., 2018, Vol. 24, no. 11, pp. 1228-1238.

89. Zhao M., Mishra L., Deng C.X. The role of TGF-β/SMAD4 signaling in cancer. Int. J. Biol. Sci., 2018, Vol. 14, no. 2, pp. 111-123.

90. Zhou X.D., Tang Z.Y., Yang B.H., Lin Z.Y., Ma Z.C., Ye S.L., Wu Z.Q., Fan J., Qin L.X., Zheng B.H. Experience of 1000 patients who underwent hepatectomy for small hepatocellular carcinoma. Cancer, 2001, Vol. 91, no. 8, pp. 1479-1486.