Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (2019RU029), Beijing, China.
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Department of Clinical Laboratory, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China.
Cancer Lett. 2024 Apr 10;587:216730. doi: 10.1016/j.canlet.2024.216730. Epub 2024 Feb 13.
Under the sustained exposure to tumor microenvironment, effector lymphocytes may transform into the suppressive populations. γδ T cells are recognized as a crucial mediator and effector of immune surveillance and thereby a promising candidate for anti-tumor immunotherapy. Emerging clinical studies implicate that some γδ T subsets play an important role in promoting tumor progression. Our previous study identified an abnormal Vδ2 T cells subset with regulatory features (Reg-Vδ2) in the patients with newly diagnosed acute myeloid leukemia (AML), and demonstrated that Reg-Vδ2 cells significantly suppressed the anti-AML effects of effector Vδ2 cells (Eff-Vδ2). The molecular mechanism underlying the subset transformation of Vδ2 cells remains unclear. Here, we found that the expression and activity of STAT5 were significantly induced in Reg-Vδ2 cells compared with Eff-Vδ2 cells, which was consistent with the differences found in primary Vδ2 cells between AML patients and healthy donors. In-vitro experiments further indicated that STAT5 was required for the induction of Reg-Vδ2 cells. The combined immunophenotypical and functional assays showed that blockage of STAT5 alleviated the immunosuppressive effect of Reg-Vδ2 cells on Eff-Vδ2 cells and enhanced the anti-AML capacity of Vδ2 cells from health donors and AML patients. Collectively, these results suggest that STAT5 acts as a critical regulator in the transformation of effector Vδ2 cells into a subset with immunosuppressive characteristics, providing a potential target for the improvement the efficacy of γδ T cells-based immunotherapy to treat AML and other hematologic malignancies.
在持续暴露于肿瘤微环境下，效应淋巴细胞可能会转化为抑制性群体。γδ T 细胞被认为是免疫监视的关键介质和效应细胞，因此是抗肿瘤免疫治疗的有前途的候选者。新兴的临床研究表明，一些 γδ T 亚群在促进肿瘤进展中发挥重要作用。我们之前的研究在新诊断的急性髓系白血病（AML）患者中鉴定出具有调节功能（Reg-Vδ2）的异常 Vδ2 T 细胞亚群，并证明 Reg-Vδ2 细胞显著抑制效应 Vδ2 细胞（Eff-Vδ2）的抗 AML 作用。Vδ2 细胞亚群转化的分子机制尚不清楚。在这里，我们发现与 Eff-Vδ2 细胞相比，Reg-Vδ2 细胞中 STAT5 的表达和活性显著增加，这与 AML 患者和健康供体之间的原发性 Vδ2 细胞之间的差异一致。体外实验进一步表明 STAT5 是诱导 Reg-Vδ2 细胞所必需的。联合免疫表型和功能测定表明，阻断 STAT5 可减轻 Reg-Vδ2 细胞对 Eff-Vδ2 细胞的免疫抑制作用，并增强健康供体和 AML 患者的 Vδ2 细胞的抗 AML 能力。总之，这些结果表明 STAT5 作为效应 Vδ2 细胞向具有免疫抑制特征的亚群转化的关键调节剂，为提高基于 γδ T 细胞免疫疗法治疗 AML 和其他血液恶性肿瘤的疗效提供了潜在目标。
