CD59-Regulated Ras Compartmentalization Orchestrates Antitumor T-cell Immunity.
CD59-Regulated Ras Compartmentalization Orchestrates Antitumor T-cell Immunity.
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CD59 调节的 Ras 区室化协调抗肿瘤 T 细胞免疫
DOI：
10.1158/2326-6066.cir-21-1072
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发表时间：
2022-12-02
影响因子：
10.1
通讯作者：
中科院分区：
文献类型：
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作者：
The subcellular compartmentalization of Ras is regulated by interacting with intracellular CD59. CD59 deficiency results in reduced trafficking of Ras to the plasma membrane in T cells, thus inducing increased T-cell signal transduction and antitumor activity. 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 subcellular compartmentalization of Ras regulated by intracellular CD59 provides spatial selectivity for T-cell activation and a potential T cell–mediated immunotherapeutic strategy.
