Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Cancer Immunol Res. 2022 Dec 2;10(12):1475-1489. doi: 10.1158/2326-6066.CIR-21-1072.
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.
T 细胞介导的免疫疗法是一种很有前途的癌症治疗策略，但它仅在有限的人群中取得了令人满意的临床反应。因此，需要更全面地了解 T 细胞免疫反应。Ras/MAPK 途径在许多重要的信号级联中起作用，并调节包括 T 细胞发育、增殖和功能在内的多种细胞活动。在此，我们发现典型的膜结合补体调节蛋白 CD59 位于 T 细胞的细胞内，并且癌症患者的 T 细胞中细胞内形式增加。当细胞内 CD59 丰富时，它通过直接相互作用促进 Ras 向内膜的运输；相反，当 CD59 不足或缺乏时，Ras 会在内质网中被截留，从而增强 Ras/MAPK 信号和 T 细胞的激活、增殖和功能。mCd59ab 缺陷几乎完全消除了荷瘤小鼠的肿瘤生长和转移，与野生型同窝仔相比，其 CD4+和 CD8+T 细胞显著增加，并且它们的比例与肿瘤生长呈负相关。通过骨髓移植和 CD4+和 CD8+T 细胞耗竭实验，我们进一步证明了这些细胞在 mCd59ab 缺陷诱导的强大抗肿瘤活性中的关键作用。降低 CD59 表达也增强了人类 T 细胞中的 MAPK 信号和 T 细胞激活。因此，细胞内 CD59 调节的 Ras 亚细胞区室化提供了 T 细胞激活的空间选择性，并为潜在的 T 细胞介导的免疫治疗策略提供了依据。
