Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Department of Pediatrics, University of Washington, Seattle, WA, USA.
Sci Immunol. 2024 Apr 19;9(94):eadg1094. doi: 10.1126/sciimmunol.adg1094.
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), expressed granzymes, perforin, and IFN-γ. Concurrent gene expression and DNA accessibility revealed that genes encoding these functional proteins correlated with expression and motif accessibility. IFN-γ T effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ T. We also observed IFN-γ T within CD19-targeted chimeric antigen receptor T cells, which killed CD19 leukemia cells. An IFN-γ T gene signature was recapitulated in T cells from human cancers, including myeloma and lymphoma. Here, we characterize a T subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional T found in chronic viral infections. Thus, IFN-γ T represent a potential target for immunotherapy of blood cancers.
慢性抗原刺激被认为会产生功能失调的 CD8 T 细胞。在这里，我们在骨髓肿瘤微环境中鉴定出一个 CD8 T 细胞亚群，尽管其表现出明显的终末耗竭表型（T），但仍表达颗粒酶、穿孔素和 IFN-γ。同时进行的基因表达和 DNA 可及性分析表明，编码这些功能蛋白的基因与 表达和基序可及性相关。IFN-γ T 能够有效地杀伤骨髓瘤，其疗效与短暂效应器相当，疾病进展与 IFN-γ T 的数量减少相关。我们还在靶向 CD19 的嵌合抗原受体 T 细胞中观察到了 IFN-γ T，它可以杀死 CD19 白血病细胞。在包括骨髓瘤和淋巴瘤在内的人类癌症的 T 细胞中重现了 IFN-γ T 基因特征。在这里，我们描述了血液恶性肿瘤中一种 T 细胞亚群，它具有悖论性的保留功能，与慢性病毒感染中发现的功能失调的 T 细胞不同。因此，IFN-γ T 代表了血液癌症免疫治疗的一个潜在靶点。
