新的T细胞负调节分子“LSECtin/LAG-3”在黑色素瘤免疫耐受中的功能研究

As important mediators of tumor tolerance, the negative regulators of T cells immune promote the development of tumor. It is an attractive strategy to induce effective tumor specific immune responses by reversing the immune dysfunctional state in the tumor microenvironment targeting these inhibitory molecules. Our team recently discovered a novel membrane protein, LSECtin, which negatively regulates the T cell immune responses. Our data preliminarily confirmed that its putative functional receptor is LAG-3 (a known inhibitory molecule on T cell surface). Therefore, we hypothesized that the interaction between LSECtin and LAG-3 inhibits the anti-tumor immunity and promotes the development of tumor. Our recent data showed that LSECtin, which is expressed specifically by human melanoma and mouse melanoma B16 cell line, promotes the differentiation of regulatory T cells. In a mouse melanoma model, the over-expression of LSECtin on B16 cell accelerated the growth of melanoma. Next, we plan to further elucidate the function of LSECtin/LAG-3 during the immune evasion of B16 melanoma and their impact on the development of melanoma; In addition, the implication of mouse melanoma therapy by blockade of LSECtin/LAG-3 will need to be explored and developed.

T细胞负调节分子作为肿瘤免疫耐受的重要执行者，促进肿瘤的发生发展。以T细胞负调节分子作为靶标，逆转机体免疫抑制状态，诱导抗肿瘤免疫成为肿瘤防治方式的新突破。我们团队发现了一种新的T细胞负调节膜分子LSECtin,并初步确认其在在T细胞上的功能受体为LAG-3（一种已知的T细胞负调节膜分子）。因此我们推测LSECtin/LAG-3可能抑制抗肿瘤T细胞免疫，促进肿瘤的发生。我们近期研究表明：LSECtin 特异表达在黑色素瘤组织和细胞，促进调节性Treg细胞的分化；在小鼠黑色素瘤模型中，LSECtin 过表达可加快小鼠成瘤。我们希望明晰LSECtin/LAG-3这一对新的T细胞负调节分子在抗黑色素瘤免疫耐受中的功能及其对黑色素瘤发生发展的影响；探索LSECtin/LAG-3的功能性拮抗剂在小鼠黑色素瘤中的实验性治疗作用。