Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-Secreted Cytokines.
Addressing Tumor Heterogeneity by Sensitizing Resistant Cancer Cells to T cell-Secreted Cytokines.
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DOI：
10.1158/2159-8290.cd-22-1125
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发表时间：
2023-05-04
期刊：
影响因子：
28.2
通讯作者：
Wucherpfennig, Kai W.
中科院分区：
文献类型：
--
作者：
Ito, Yoshinaga;Pan, Deng;Zhang, Wubing;Zhang, Xixi;Juan, Tiffany Y.;Pyrdol, Jason W.;Kyrysyuk, Oleksandr;Doench, John G.;Liu, X. Shirley;Wucherpfennig, Kai W.
肿瘤异质性是癌症治疗（包括免疫治疗）的主要障碍。活化的 T 细胞在识别 MHC I 类 (MHC-I) 结合肽后可以有效杀死肿瘤细胞，但这种选择压力有利于 MHC-I 缺陷型肿瘤细胞的生长。我们进行了基因组规模的筛选，以发现 T 细胞介导的杀伤 MHC-I 缺陷肿瘤细胞的替代途径。自噬和 TNF 信号传导成为首要途径，Rnf31（TNF 信号传导）和 Atg5（自噬）失活使 MHC-I 缺陷的肿瘤细胞对 T 细胞衍生细胞因子的凋亡敏感。机制研究表明，抑制自噬可增强肿瘤细胞中细胞因子的促凋亡作用。来自凋亡 MHC-I 缺陷肿瘤细胞的抗原被树突状细胞有效地交叉提呈，导致产生 IFNγ 和 TNFα 的 T 细胞增强肿瘤浸润。当使用遗传或药理学方法靶向这两种途径时，具有大量 MHC-I 缺陷癌细胞的肿瘤可以由 T 细胞控制。
Tumor heterogeneity is a major barrier to cancer therapy, including immunotherapy. Activated T cells can efficiently kill tumor cells following recognition of MHC class I (MHC-I) bound peptides, but this selection pressure favors outgrowth of MHC-I deficient tumor cells. We performed a genome-scale screen to discover alternative pathways for T cell-mediated killing of MHC-I deficient tumor cells. Autophagy and TNF signaling emerged as top pathways, and inactivation of Rnf31 (TNF signaling) and Atg5 (autophagy) sensitized MHC-I deficient tumor cells to apoptosis by T cell-derived cytokines. Mechanistic studies demonstrated that inhibition of autophagy amplified pro-apoptotic effects of cytokines in tumor cells. Antigens from apoptotic MHC-I deficient tumor cells were efficiently cross-presented by dendritic cells, resulting in heightened tumor infiltration by IFNγ and TNFα-producing T cells. Tumors with a substantial population of MHC-I deficient cancer cells could be controlled by T cells when both pathways were targeted using genetic or pharmacological approaches.