Modulating hepatic iNKT cell accumulation and maturation via chemokine receptor CXCR6 for liver cancer prevention and treatment
Final Report Abstract
This project analyzed (i) the functional role of CXCR6-dependent iNKT accumulation in inflammationinduced vs. inflammation-inducing liver cancer (mouse HCC models); (ii) cellular mechanisms of antior pro-tumoral iNKT cell effects (bone marrow transplantation, adoptive transfer); (iii) molecular mechanisms of iNKT cells in hepatocarcinogenesis (esp. iNKT - macrophage and iNKT – tumor cell interactions); (iv) therapeutic interventions targeting iNKT cells in liver cancer in vivo (using αGal- Cer); (v) translation (CXCR6, iNKT cells) into human hepatocarcinogenesis. All planned aspects of the proposal could be successfully addressed. We could demonstrated that, using two independent models of primary liver cancer in mice, CXCR6- dependent NKT- and CD4+ T cells exert essential roles in suppressing hepatocarcinogenesis by promoting the elimination of senescent, pre-malignant hepatocytes. While similar observations were confirmed in human HCC samples, the mechanistic contribution of CD4+ T and NKT cells compared to other CXCR6þ immune cells (eg, MAIT cells) in human HCC remains to be clarified (and is currently explored in follow-up projects). Collectively, CXCR6 has a previously unrecognized function in tumor surveillance via NKT- and CD4+ T cell-dependent senescence control, indicating that novel anti-inflammatory or anti-fibrotic immune modulatory therapies in the liver need to be validated regarding effects on hepatocarcinogenesis.
Publications
- Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease. Hepatology. 2016 Apr;63(4):1310-24
Bartneck M, Fech V, Ehling J, Govaere O, Warzecha KT, Hittatiya K, Vucur M, Gautheron J, Luedde T, Trautwein C, Lammers T, Roskams T, Jahnen-Dechent W, Tacke F
(See online at https://doi.org/10.1002/hep.28418) - Immunomodulatory Therapy of Inflammatory Liver Disease Using Selectin-Binding Glycopolymers. ACS Nano. 2017; 11(10):9689-9700
Bartneck M, Schlößer CT, Barz M, Zentel R, Trautwein C, Lammers T, Tacke F
(See online at https://doi.org/10.1021/acsnano.7b04630) - Targeting distinct myeloid cell populations in vivo using polymers, liposomes and microbubbles. Biomaterials. 2017; 114:106-120
Ergen C, Heymann F, Al Rawashdeh W, Gremse F, Bartneck M, Panzer U, Pola R, Pechar M, Storm G, Mohr N, Barz M, Zentel R, Kiessling F, Trautwein C, Lammers T, Tacke F
(See online at https://doi.org/10.1016/j.biomaterials.2016.11.009) - Dynamic plasticity of macrophage functions in diseased liver. Cell Immunol. 2018; 330:175-182
Ritz T, Krenkel O, Tacke F
(See online at https://doi.org/10.1016/j.cellimm.2017.12.007) - Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018; 67(4):1270-1283
Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, Liepelt A, Lefebvre E, Luedde T, Hellerbrand C, Weiskirchen R, Longerich T, Costa IG, Anstee QM, Trautwein C, Tacke F
(See online at https://doi.org/10.1002/hep.29544) - CXCR6 Inhibits Hepatocarcinogenesis by Promoting Natural Killer T- and CD4(+) T-Cell-Dependent Control of Senescence. Gastroenterology. 2019; 156(6):1877-1889
Mossanen JC, Kohlhepp M, Wehr A, Krenkel O, Liepelt A, Roeth AA, Möckel D, Heymann F, Lammers T, Gassler N, Hermann J, Jankowski J, Neumann UP, Luedde T, Trautwein C, Tacke F
(See online at https://doi.org/10.1053/j.gastro.2019.01.247) - CXCR6 protects from inflammation and fibrosis in NEMO(LPC-KO) mice. Biochim Biophys Acta Mol Basis Dis. 2019; 1865(2):391-402
Liepelt A, Wehr A, Kohlhepp M, Mossanen JC, Kreggenwinkel K, Denecke B, Costa IG, Luedde T, Trautwein C, Tacke F
(See online at https://doi.org/10.1016/j.bbadis.2018.11.020) - Single Cell RNA Sequencing Identifies Subsets of Hepatic Stellate Cells and Myofibroblasts in Liver Fibrosis. Cells. 2019; 8(5):503
Krenkel O, Hundertmark J, Ritz TP, Weiskirchen R, Tacke F
(See online at https://doi.org/10.3390/cells8050503) - The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers. Cell Mol Gastroenterol Hepatol. 2019; 7(2):371-390
Bartneck M, Schrammen PL, Möckel D, Govaere O, Liepelt A, Krenkel O, Ergen C, McCain MV, Eulberg D, Luedde T, Trautwein C, Kiessling F, Reeves H, Lammers T, Tacke F
(See online at https://doi.org/10.1016/j.jcmgh.2018.10.007) - Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages. J Hepatol. 2020; 73(4):757-770
Lefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, de Muynck K, Heymann F, Adarbes V, Defrêne E, Estivalet C, Geerts A, Devisscher L, Wettstein G, Tacke F
(See online at https://doi.org/10.1016/j.jhep.2020.04.025) - Myeloid cells in liver and bone marrow acquire a functionally distinct inflammatory phenotype during obesity-related steatohepatitis. Gut. 2020; 69(3):551-563
Krenkel O, Hundertmark J, Abdallah AT, Kohlhepp M, Puengel T, Roth T, Branco DPP, Mossanen JC, Luedde T, Trautwein C, Costa IG, Tacke F
(See online at https://doi.org/10.1136/gutjnl-2019-318382) - The role of the innate immune system in the development and treatment of hepatocellular carcinoma. Hepat Oncol. 2020; 7(1):HEP17
Roderburg C, Wree A, Demir M, Schmelzle M, Tacke F
(See online at https://doi.org/10.2217/hep-2019-0007) - Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma. Cancers (Basel). 2021; 13(4):730
Peiseler M, Tacke F
(See online at https://doi.org/10.3390/cancers13040730) - Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion. Cell Mol Gastroenterol Hepatol. 2021; 11(2):327-347
Bartneck M, Koppe C, Fech V, Warzecha KT, Kohlhepp M, Huss S, Weiskirchen R, Trautwein C, Luedde T, Tacke F
(See online at https://doi.org/10.1016/j.jcmgh.2020.08.012)
