Cancer cells can evade immune recognition by losing major histocompatibility complex (MHC) class I. Hence, MHC class I-negative cancers represent the most challenging cancers to treat. Chemotherapeutic drugs not only directly kill tumors but also modulate the tumor immune microenvironment. However, it remains unknown whether chemotherapy-treated cancer cells can activate CD8 T cells independent of tumor-derived MHC class I and whether such MHC class I-independent CD8 T-cell activation can be exploited for cancer immunotherapy. Here, we showed that chemotherapy-treated cancer cells directly activated CD8 T cells in an MHC class I-independent manner and that these activated CD8 T cells exhibit virtual memory (VM) phenotypes. Consistently, in vivo chemotherapeutic treatment preferentially increased tumor-infiltrating VM CD8 T cells. Mechanistically, MHC class I-independent activation of CD8 T cells requires cell-cell contact and activation of the PI3K pathway. VM CD8 T cells contribute to a superior therapeutic effect on MHC class I-deficient tumors. Using humanized mouse models or primary human CD8 T cells, we also demonstrated that chemotherapy-treated human lymphomas activated VM CD8 T cells independent of tumor-derived MHC class I. In conclusion, CD8 T cells can be directly activated in an MHC class I-independent manner by chemotherapy-treated cancers, and these activated CD8 T cells may be exploited for developing new strategies to treat MHC class I-deficient cancers.

中文翻译：

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由化疗剂处理的癌细胞诱导的虚拟记忆 CD8 T 细胞的 MHC I 类非依赖性激活。

癌细胞可以通过失去主要组织相容性复合体 (MHC) I 类来逃避免疫识别。因此，MHC I 类阴性癌症是最具挑战性的癌症治疗。化疗药物不仅可以直接杀死肿瘤，还可以调节肿瘤免疫微环境。然而，化疗治疗的癌细胞是否可以独立于肿瘤衍生的 MHC I 类激活 CD8 T 细胞以及这种不依赖于 MHC I 类的 CD8 T 细胞激活是否可用于癌症免疫治疗仍然未知。在这里，我们发现化疗处理的癌细胞以不依赖 MHC I 类的方式直接激活 CD8 T 细胞，并且这些激活的 CD8 T 细胞表现出虚拟记忆 (VM) 表型。一致地，体内化疗治疗优先增加肿瘤浸润性VM CD8 T细胞。机械地，CD8 T 细胞的 MHC I 类非依赖性激活需要细胞间接触和 PI3K 通路的激活。VM CD8 T 细胞有助于对 MHC I 类缺陷型肿瘤产生卓越的治疗效果。使用人源化小鼠模型或原代人 CD8 T 细胞，我们还证明了化疗治疗的人淋巴瘤激活 VM CD8 T 细胞独立于肿瘤衍生的 MHC I 类。总之，CD8 T 细胞可以在 MHC I 类中直接激活这些活化的 CD8 T 细胞可用于开发治疗 MHC I 类缺陷型癌症的新策略。