SLAM家族受体调控抗肿瘤免疫的机制研究

以PD-1治疗为代表的免疫检查点阻断依赖于肿瘤浸润CD8+T细胞，但是许多患者肿瘤浸润CD8+ T细胞数目较少，这是影响PD-1等免疫治疗的重要因素。因此寻找促进CD8+ T细胞扩增和功能的新机制迫在眉睫。肿瘤免疫微环境中还存在多种固有免疫细胞，以巨噬细胞、树突状细胞为代表的抗原呈递细胞，他们通过吞噬，加工并将肿瘤抗原呈递给T细胞以促进T细胞扩增及活化。SLAM家族受体由7个成员组成，我们前期发现SLAM家族受体缺失可导致造血实体瘤几乎完全消退，并初步证明缺失SLAM家族受体增强抗原呈递作用，从而间接增强CD8+ T细胞抗肿瘤。该申请拟进一步探索SLAM家族受体调节抗肿瘤反应的机制、寻找关键SLAM家族成员，从而探究SLAM家族受体抗肿瘤的应用潜力。因此，该研究有望揭示一种固有细胞“免疫检查点”间接促进抗肿瘤的新机制，该机制或许为“根治肿瘤”提供新策略。

Immune checkpoint blockade, represented by PD-1 therapy, enhances the activation and function of T cells by reducing the inhibitory signal of CD8+ T cells. However, the number of tumor infiltrating CD8+ T cells is very seldom in most patients, which is an important factor affecting immunotherapy, such as PD-1. Thus, it is urgent to find a new mechanism to promote the expansion and function of CD8+ T cells. There are many kinds of innate immune cells in tumor immune microenvironment, such as macrophages and dendritic cells, which can phagocytosis, process and present tumor antigen to T cells to promote T cells expansion and activation. SLAM family receptors are composed of seven members. We found that the deletion of SLAM family receptors can lead to almost complete regression of hematopoietic solid tumors, and preliminarily proved that the deletion of SLAM family receptors can enhance antigen presentation thus indirectly enhance CD8+ T cells-dependent anti-tumor immunity. We intend to further explore the mechanisms of SLAM family receptors regulating anti-tumor response and find key SLAM family members, so as to explore the anti-tumor application. Therefore, this study is expected to reveal a new mechanism of innate cell "immune checkpoint" indirectly promoting anti-tumor response, which may provide a new strategy for radical curing cancers.