CD59-Regulated Ras Compartmentalization Orchestrates Antitumor T-cell Immunity

作者：Luying Li, Peipei Ding, Xinyue Lv, Suhong Xie, Ling Li, Jianfeng Chen, Danlei Zhou, Xiaochao Wang, Qi Wang, Wei Zhang, Yanqing Xu, Renquan Lu, Weiguo Hu · 发表于：Cancer Immunology Research · 年份：2022 · DOI：10.1158/2326-6066.cir-21-1072 · 被引用次数：12 · 研究领域：Immune Cell Function and Interaction、Phagocytosis and Immune Regulation、T-cell and B-cell Immunology

T cell-mediated immunotherapy represents a promising strategy for cancer treatment; however, it has achieved satisfactory clinical responses in only a limited population. Thus, a broader view of the T-cell immune response is required. The Ras/MAPK pathway operates in many important signaling cascades and regulates multiple cellular activities, including T-cell development, proliferation, and function. Herein, we found that the typical membrane-bound complement regulatory protein CD59 is located intracellularly in T cells and that the intracellular form is increased in the T cells of patients with cancer. When intracellular CD59 is abundant, it facilitates Ras transport to the inner plasma membrane via direct interaction; in contrast, when CD59 is insufficient or deficient, Ras is arrested in the Golgi, thus enhancing Ras/MAPK signaling and T-cell activation, proliferation, and function. mCd59ab deficiency almost completely abolished tumor growth and metastasis in tumor-bearing mice, in which CD4+ and CD8+ T cells were significantly increased compared with their proportions in wild-type littermates, and their proportions were inversely correlated with tumor growth. Using bone marrow transplantation and CD4+ and CD8+ T-cell depletion assays, we further demonstrated the critical roles of these cells in the potent antitumor activity induced by mCd59ab deficiency. Reducing CD59 expression also enhanced MAPK signaling and T-cell activation in human T cells. Therefore, the subcellul...