CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4+ T-Cell–Dependent Control of Senescence

Gastroenterology

Volumn 156, Issue 6, 2019, Pages 1877-1889.e4

  Mossanen, Jana C ^a   Kohlhepp, Marlene ^a   Wehr, Alexander ^a,b   Krenkel, Oliver ^a   Liepelt, Anke ^a   Roeth, Anjali A ^a   Möckel, Diana ^a   Heymann, Felix ^a,b   Lammers, Twan ^a   Gassler, Nikolaus ^c   Hermann, Juliane ^a   Jankowski, Joachim ^a   Neumann, Ulf P ^a   Luedde, Tom ^a   Trautwein, Christian ^a   Tacke, Frank ^a,b  

^a UNIVERSITY HOSPITAL RWTH AACHEN   (Germany)

^b CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^c Clinic of Braunschweig   (Germany)

Author keywords

Chemokine; Liver Cancer; NKT Cells; Senescence

Indexed keywords

ALPHA GALACTOSYLCERAMIDE; CHEMOKINE RECEPTOR CXCR6; DIETHYLNITROSAMINE; GAMMA INTERFERON; GRANZYME B; INTERLEUKIN 17; INTERLEUKIN 2; INTERLEUKIN 21; MESSENGER RNA; TUMOR NECROSIS FACTOR; ALPHA-GALACTOSYLCERAMIDE; CXCR6 PROTEIN, MOUSE; GALACTOSYLCERAMIDE; NEMO PROTEIN, MOUSE; SIGNAL PEPTIDE;

ADOPTIVE TRANSFER; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE MARROW TRANSPLANTATION; CANCER INHIBITION; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL AGING; CELL TRANSFER; CLINICAL ARTICLE; CONTROLLED STUDY; FLOW CYTOMETRY; GENE EXPRESSION; HUMAN; HUMAN TISSUE; IMMUNE RESPONSE; IMMUNOHISTOCHEMISTRY; IMMUNOSURVEILLANCE; LEUKOCYTE; LIVER CANCER; LIVER CARCINOGENESIS; LIVER CELL; LIVER CIRRHOSIS; LIVER HISTOLOGY; LYMPHOCYTE; MALE; MOUSE; NATURAL KILLER CELL; NATURAL KILLER T CELL; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; TUMOR IMMUNITY; TUMOR NUMBER; TUMOR VOLUME; UPREGULATION; WHOLE BODY RADIATION; ANIMAL; C57BL MOUSE; CARCINOGENESIS; CHEMICALLY INDUCED; DISEASE EXACERBATION; DRUG EFFECT; GENETICS; IMMUNOLOGY; KNOCKOUT MOUSE; LIVER CELL CARCINOMA; LIVER TUMOR; LYMPHOCYTE ACTIVATION; METABOLISM; PATHOLOGY; PHYSIOLOGY;

ANIMALS; CARCINOGENESIS; CARCINOMA, HEPATOCELLULAR; CD4-POSITIVE T-LYMPHOCYTES; CELLULAR SENESCENCE; DIETHYLNITROSAMINE; DISEASE PROGRESSION; GALACTOSYLCERAMIDES; HEPATOCYTES; HUMANS; IMMUNOLOGIC SURVEILLANCE; INTERFERON-GAMMA; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LIVER CIRRHOSIS; LIVER NEOPLASMS; LYMPHOCYTE ACTIVATION; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; NATURAL KILLER T-CELLS; RECEPTORS, CXCR6; TUMOR BURDEN; TUMOR NECROSIS FACTOR-ALPHA;

EID: 85064327066     PISSN: 00165085     EISSN: 15280012     Source Type: Journal    
DOI: 10.1053/j.gastro.2019.01.247     Document Type: Article

References (43)

1. Lafaro, K.J., Demirjian, A.N., Pawlik, T.M., Epidemiology of hepatocellular carcinoma. Surg Oncol Clin N Am 24 (2015), 1–17.
2. El-Serag, H.B., Hepatocellular carcinoma. N Engl J Med 365 (2011), 1118–1127.
3. Hernandez-Gea, V., Toffanin, S., Friedman, S.L., et al. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144 (2013), 512–527.
4. Mantovani, A., Allavena, P., Sica, A., et al. Cancer-related inflammation. Nature 454 (2008), 436–444.
5. El-Khoueiry, A.B., 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 389 (2017), 2492–2502.
6. Heymann, F., Tacke, F., Immunology in the liver–from homeostasis to disease. Nat Rev Gastroenterol Hepatol 13 (2016), 88–110.
7. Rotman, Y., Sanyal, A.J., Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut 66 (2017), 180–190.
8. Wehr, A., Baeck, C., Ulmer, F., et al. Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. PLoS One, 9, 2014, e112327.
9. Wehr, A., Baeck, C., Heymann, F., et al. Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis. J Immunol 190 (2013), 5226–5236.
10. + NKT cells patrolling liver sinusoids. PLoS Biol, 3, 2005, e113.
11. Gao, Q., Zhao, Y.J., Wang, X.Y., et al. CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res 72 (2012), 3546–3556.
12. Heydtmann, M., Lalor, P.F., Eksteen, J.A., et al. CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J Immunol 174 (2005), 1055–1062.
13. Unutmaz, D., Xiang, W., Sunshine, M.J., et al. The primate lentiviral receptor Bonzo/STRL33 is coordinately regulated with CCR5 and its expression pattern is conserved between human and mouse. J Immunol 165 (2000), 3284–3292.
14. Bettermann, K., Vucur, M., Haybaeck, J., et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 17 (2010), 481–496.
15. Schneider, C., Teufel, A., Yevsa, T., et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61 (2012), 1733–1743.
16. Mossanen, J.C., Krenkel, O., Ergen, C., et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology 64 (2016), 1667–1682.
17. Cubero, F.J., Singh, A., Borkham-Kamphorst, E., et al. TNFR1 determines progression of chronic liver injury in the IKKgamma/Nemo genetic model. Cell Death Differ 20 (2013), 1580–1592.
18. Schneider, A.T., Gautheron, J., Feoktistova, M., et al. RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer. Cancer Cell 31 (2017), 94–109.
19. Ogrodnik, M., Miwa, S., Tchkonia, T., et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun, 8, 2017, 15691.
20. Krizhanovsky, V., Yon, M., Dickins, R.A., et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134 (2008), 657–667.
21. Koch, A., Zimmermann, H.W., Gassler, N., et al. Clinical relevance and cellular source of elevated soluble urokinase plasminogen activator receptor (suPAR) in acute liver failure. Liver Int 34 (2014), 1330–1339.
22. Lee, J.S., Chu, I.S., Mikaelyan, A., et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 36 (2004), 1306–1311.
23. Liepelt, A., Wehr, A., Kohlhepp, M., et al. CXCR6 protects from inflammation and fibrosis in NEMO(LPC-KO) mice. Biochim Biophys Acta Mol Basis Dis 1865 (2019), 391–402.
24. Kang, T.W., Yevsa, T., Woller, N., et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479 (2011), 547–551.
25. Eggert, T., Wolter, K., Ji, J., et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30 (2016), 533–547.
26. Braumuller, H., Wieder, T., Brenner, E., et al. T-helper-1-cell cytokines drive cancer into senescence. Nature 494 (2013), 361–365.
27. Quezada, S.A., Simpson, T.R., Peggs, K.S., et al. Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J Exp Med 207 (2010), 637–650.
28. Germanov, E., Veinotte, L., Cullen, R., et al. Critical role for the chemokine receptor CXCR6 in homeostasis and activation of CD1d-restricted NKT cells. J Immunol 181 (2008), 81–91.
29. Luedde, T., Beraza, N., Kotsikoris, V., et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11 (2007), 119–132.
30. Llovet, J.M., Zucman-Rossi, J., Pikarsky, E., et al. Hepatocellular carcinoma. Nat Rev Dis Primers, 2, 2016, 16018.
31. Prieto, J., Melero, I., Sangro, B., Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 12 (2015), 681–700.
32. Kuilman, T., Michaloglou, C., Mooi, W.J., et al. The essence of senescence. Genes Dev 24 (2010), 2463–2479.
33. Jackson, J.G., Pant, V., Li, Q., et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell 21 (2012), 793–806.
34. Acosta, J.C., Banito, A., Wuestefeld, T., et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15 (2013), 978–990.
35. Mossanen, J.C., Tacke, F., Role of lymphocytes in liver cancer. Oncoimmunology, 2, 2013, e26468.
36. Anson, M., Crain-Denoyelle, A.M., Baud, V., et al. Oncogenic beta-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J Clin Invest 122 (2012), 586–599.
37. Margalit, M., Shibolet, O., Klein, A., et al. Suppression of hepatocellular carcinoma by transplantation of ex-vivo immune-modulated NKT lymphocytes. Int J Cancer 115 (2005), 443–449.
38. Iannello, A., Thompson, T.W., Ardolino, M., et al. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med 210 (2013), 2057–2069.
39. Liew, P.X., Lee, W.Y., Kubes, P., iNKT cells orchestrate a switch from inflammation to resolution of sterile liver injury. Immunity 47 (2017), 752–765.
40. Chew, V., Tow, C., Teo, M., et al. Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 52 (2010), 370–379.
41. Xiao, Y.S., Gao, Q., Xu, X.N., et al. Combination of intratumoral invariant natural killer T cells and interferon-gamma is associated with prognosis of hepatocellular carcinoma after curative resection. PLoS One, 8, 2013, e70345.
42. Lee, J.H., Lee, J.H., Lim, Y.S., et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148 (2015), 1383–1391.
43. Marra, F., Tacke, F., Roles for chemokines in liver disease. Gastroenterology 147 (2014), 577–594.