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

肝细胞癌（HCC）通常发生在慢性炎症的肝脏中，但也会引起（抗肿瘤）免疫反应。使用二乙基亚硝胺（DEN）诱导的小鼠肝癌，我们以前证明，不同的淋巴细胞群体抑制肝癌发生。不变的自然杀伤T（iNKT）细胞是肝脏中的主要淋巴细胞亚群。我们最近发现，肝iNKT细胞利用趋化因子受体CXCR 6在损伤的肝脏中积累并使炎症持续存在。因此，我们假设CXCR 6依赖性iNKT细胞代表了一种限制体内肝癌发生的新途径。事实上，Cxcr 6缺陷小鼠在DEN模型中发展出更多进行性肝肿瘤[自己未发表的观察结果]。该项目将分析（i）CXCR 6依赖性iNKT积累在炎症诱导的肝癌与炎症诱导的肝癌中的功能作用（ii）抗肿瘤或促肿瘤iNKT细胞作用的细胞机制（iii）iNKT细胞在肝癌发生中的分子机制（特别是iNKT -巨噬细胞和iNKT -肿瘤细胞相互作用）;（iv）在体内肝癌中靶向iNKT细胞的治疗性干预（使用α-Gal-Cer、抗CXCL 16和重组CXCL 16）;（V）翻译（CXCR 6、iNKT细胞）进入人肝癌发生。总的来说，我们将探索通过CXCR 6调节肝脏iNKT细胞积累是否是肝癌预防和治疗的新方法。

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 In fact, Cxcr6-deficient mice develop more progressive liver tumors in the DEN model [own unpublished ob-servations].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.