Chronic antigen stimulation is thought to generate dysfunctional CD8 T cells. Here, we identify a CD8 T cell subset in the bone marrow tumor microenvironment that, despite an apparent terminally exhausted phenotype (T PHEX ), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with BATF expression and motif accessibility. IFN-γ + T PHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ + T PHEX . We also observed IFN-γ + T PHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19 + leukemia cells. An IFN-γ + T PHEX gene signature was recapitulated in T EX cells from human cancers, including myeloma and lymphoma. Here, we characterize a T EX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T EX found in chronic viral infections. Thus, IFN-γ + T PHEX represent a potential target for immunotherapy of blood cancers.

中文翻译：

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具有终末耗竭表型的 TIM-3 + CD8 T 细胞在血液恶性肿瘤中保留功能能力


慢性抗原刺激被认为会产生功能失调的 CD8 T 细胞。在这里，我们鉴定了骨髓肿瘤微环境中的 CD8 T 细胞亚群，尽管其具有明显的终末耗尽表型（T菲克斯)，表达颗粒酶、穿孔素和 IFN-γ。同时的基因表达和 DNA 可及性表明，编码这些功能蛋白的基因与巴特夫表达和主题的可访问性。干扰素-γ +时间菲克斯有效杀死骨髓瘤，其疗效与短暂效应器相当，并且疾病进展与 IFN-γ 的数量缺陷相关+时间菲克斯。我们还观察到 IFN-γ +时间菲克斯在 CD19 靶向嵌合抗原受体 T 细胞内，杀死 CD19 +白血病细胞。干扰素-γ +时间菲克斯基因签名在 T 中重述前任来自人类癌症的细胞，包括骨髓瘤和淋巴瘤。在这里，我们描述一个T前任血液系统恶性肿瘤中的一个子集，矛盾地保留了功能，并且与功能失调的 T 不同前任见于慢性病毒感染。因此，干扰素-γ +时间菲克斯代表了血癌免疫治疗的潜在靶点。