American Association for Cancer Research

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Supplementary Data from CD59-Regulated Ras Compartmentalization Orchestrates Antitumor T-cell Immunity

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posted on 2023-04-04, 02:02 authored by 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
Supplementary Data from CD59-Regulated Ras Compartmentalization Orchestrates Antitumor T-cell Immunity


National Natural Science Foundation of China (NSFC)



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.

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