Modulating hepatic iNKT cell accumulation and maturation via chemokine receptor CXCR6 for liver cancer prevention and treatment

• Applicant: Professor Frank Tacke, Ph.D.
• Subject Area: Gastroenterology
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269868459

• Final Report Year: 2021

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
  
• 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
  
• 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
  
• Dynamic plasticity of macrophage functions in diseased liver. Cell Immunol. 2018; 330:175-182
  Ritz T, Krenkel O, Tacke F
  
• 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
  
• 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
  
• 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
  
• 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
  
• 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
  
• 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
  
• 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
  
• 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
  
• Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma. Cancers (Basel). 2021; 13(4):730
  Peiseler M, Tacke F
  
• 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