Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
Oncoimmunology. 2022 Aug 20;11(1):2114740. doi: 10.1080/2162402X.2022.2114740. eCollection 2022.
ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of FF-ATP synthase. ATPIF1 activity remains unknown in the control of immune activity of T cells. In this study, we identified ATPIF1 activity in the induction of CD8 T cell function in tumor models through genetic approaches. ATPIF1 gene inactivation impaired the immune activities of CD8 T cells leading to quick tumor growth (B16 melanoma and Lewis lung cancer) in ATPIF1-KO mice. The KO T cells exhibited a reduced activity in proliferation and IFN-γ secretion with metabolic reprogramming of increased glycolysis and decreased oxidative phosphorylation (OXPHOS) after activation. T cell exhaustion was increased in the tumor infiltrating leukocytes (TILs) of KO mice as revealed by the single-cell RNA sequencing (scRNA-seq) and confirmed by flow cytometry. In contrast, ATPIF1 overexpression in T cells increased expression of IFN-γ and Granzyme B, subset of central memory T cells in CAR-T cells, and survival rate of NALM-6 tumor-bearing mice. These data demonstrate that ATPIF1 deficiency led to tumor immune deficiency through induction of T cell exhaustion. ATPIF1 overexpression enhanced the T cell tumor immunity. Therefore, ATPIF1 is a potential molecular target in the modulation of antitumor immunity of CD8 T cells in cancer immunotherapy. Induction of ATPIF1 activity may promote CAR-T activity in cancer therapy.
ATP 合酶抑制因子 1（ATPIF1）是一种具有抑制 FF-ATP 合酶活性的线粒体蛋白。ATPIF1 活性在调节 T 细胞免疫活性方面的作用尚不清楚。在这项研究中，我们通过遗传方法鉴定了肿瘤模型中 CD8 T 细胞功能诱导中的 ATPIF1 活性。ATPIF1 基因失活会损害 CD8 T 细胞的免疫活性，导致 ATPIF1-KO 小鼠中肿瘤快速生长（B16 黑色素瘤和 Lewis 肺癌）。KO 小鼠的 T 细胞增殖和 IFN-γ 分泌活性降低，激活后糖酵解增加，氧化磷酸化（OXPHOS）减少，表现出代谢重编程。单细胞 RNA 测序（scRNA-seq）显示并通过流式细胞术证实，KO 小鼠肿瘤浸润白细胞（TIL）中的 T 细胞耗竭增加。相比之下，T 细胞中 ATPIF1 的过表达增加了 CAR-T 细胞中 IFN-γ 和 Granzyme B 的表达，以及 NALM-6 荷瘤小鼠的存活率。这些数据表明，ATPIF1 缺乏通过诱导 T 细胞耗竭导致肿瘤免疫缺陷。ATPIF1 的过表达增强了 T 细胞的肿瘤免疫。因此，ATPIF1 是癌症免疫治疗中调节 CD8 T 细胞抗肿瘤免疫的潜在分子靶点。诱导 ATPIF1 活性可能会促进癌症治疗中的 CAR-T 活性。
