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

Hepatocellular carcinoma (HCC) commonly arises in chronically inflamed livers, but also provokes (anti-tumoral) immune responses. Using diethylnitrosamine (DEN)-induced liver cancer in mice, we previously demonstrated that distinct lymphocyte populations suppress hepatocarcinogenesis. Invariant natural killer T (iNKT) cells are a predominant lymphocyte subset in the liver. We recently found that hepatic iNKT cells employ the chemokine receptor CXCR6 to accumulate in injured liver and perpetuate inflammation. We thus hypothesized that CXCR6-dependent iNKT cells represent a novel pathway to limit hepatocarcinogenesis in vivo. In fact, Cxcr6-deficient mice develop more progressive liver tumors in the DEN model [own unpublished ob-servations]. This project will analyze (i) the functional role of CXCR6-dependent iNKT accumulation in inflammation-induced vs. inflammation-inducing liver cancer (three HCC models); (ii) cellular mechanisms of anti- or 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 alpha-Gal-Cer, anti-CXCL16 and recombinant CXCL16); (v) translation (CXCR6, iNKT cells) into human hepatocarcinogenesis. Collectively, we will explore if modulating hepatic iNKT cell accumulation via CXCR6 is a novel approach for liver cancer prevention and treatment.

• DFG Programme: Research Grants