PDF(Pubmed)
Abstract：
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 (TPHEX), 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+ TPHEX effectively killed myeloma with comparable efficacy to transitory effectors, and disease progression correlated with numerical deficits in IFN-γ+ TPHEX. We also observed IFN-γ+ TPHEX within CD19-targeted chimeric antigen receptor T cells, which killed CD19+ leukemia cells. An IFN-γ+ TPHEX gene signature was recapitulated in TEX cells from human cancers, including myeloma and lymphoma. Here, we characterize a TEX subset in hematological malignancies that paradoxically retains function and is distinct from dysfunctional TEX found in chronic viral infections. Thus, IFN-γ+ TPHEX represent a potential target for immunotherapy of blood cancers.
摘要：
慢性抗原刺激被认为产生功能失调的CD8T细胞。这里,我们在骨髓肿瘤微环境中发现了一个CD8T细胞亚群，尽管有明显的终末耗尽表型（TPHEX），表达的颗粒酶，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BATF表达和基序可及性相关。IFN-γ+TPHEX有效杀死骨髓瘤，疗效与短暂效应物相当，疾病进展与IFN-γ+TPHEX的数量缺陷相关。我们还在CD19靶向的嵌合抗原受体T细胞中观察到IFN-γ+TPHEX，杀死CD19+白血病细胞。IFN-γ+TPHEX基因签名在来自人类癌症的TEX细胞中被概括,包括骨髓瘤和淋巴瘤.这里,我们在血液系统恶性肿瘤中描述了一个TEX子集,该子集矛盾地保留了功能,并且与慢性病毒感染中发现的功能失调的TEX不同.因此，IFN-γ+TPHEX代表血癌免疫治疗的潜在靶标。
