Background: Venetoclax-based combination therapies have provided treatment options for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, venetoclax resistance is common, and for such patients, the prognosis is dismal, and treatment approaches with different mechanisms of action are urgently needed. γδ T cells are a promising candidate owing to their good safety profile and cytotoxic effects in various types of cancers but are mostly unstudied in AML. Methods: Here we used flow cytometry to profile the subtype and memory phenotype of peripheral blood γδ T cells in AML patients and investigate the feasibility of using donor-derived Vγ9Vδ2 T cells to treat AML as both a single agent and in combination with venetoclax. Additionally, we used bioluminescence imaging to examine the effect of donor-derived Vγ9Vδ2 T cells on AML xenograft models alone and in combination with venetoclax. Results: We observed that Vδ2 T cells were less abundant and the TEMRA (terminally differentiated effector memory) phenotype was more prevalent as compared with that of healthy donors, suggesting that replenishing patients with Vδ2 T cells may be an effective treatment option. We found that donor-derived Vγ9Vδ2 T cells that Vγ9Vδ2 T cells efficiently induced apoptosis in AML cells from eight cell lines and three primary cultures in an effector-to-target cell ratio-dependent manner. Moreover, Vγ9Vδ2 T cells showed potent cytotoxicity against the venetoclax-resistant OCI-AML3 cell line and remained potent in the presence of venetoclax. Treatment with Vγ9Vδ2 T cells significantly extended survival in two AML xenograft models established with the aggressive Molm-13 and the venetoclax-resistant OCI-AML3 cell lines. An additive effect of venetoclax and Vγ9Vδ2 T cells was observed in the latter model. Conclusions: Overall, these findings suggest Vγ9Vδ2 T cells as a promising “off-the-shelf” immunotherapy approach for AML patients, especially for patients with venetoclax-resistant disease.
背景：基于维奈托克的联合疗法为不适合强化化疗的急性髓系白血病（AML）患者提供了治疗选择。然而，维奈托克耐药现象普遍存在，此类患者预后极差，亟需开发具有不同作用机制的治疗方法。γδ T细胞因其良好的安全性及在多种癌症中的细胞毒性效应而成为一种有前景的候选疗法，但在AML领域的研究尚不充分。 方法：本研究采用流式细胞术分析AML患者外周血γδ T细胞的亚型及记忆表型特征，并探讨供体来源的Vγ9Vδ2 T细胞单药或联合维奈托克治疗AML的可行性。同时，通过生物发光成像技术评估供体来源Vγ9Vδ2 T细胞单药及联合维奈托克对AML异种移植模型的作用。 结果：与健康供体相比，AML患者Vδ2 T细胞数量减少，终末分化效应记忆（TEMRA）表型比例升高，提示补充Vδ2 T细胞可能成为有效的治疗策略。研究发现，供体来源的Vγ9Vδ2 T细胞能以效应细胞-靶细胞比例依赖的方式，有效诱导8个细胞系和3个原代培养AML细胞的凋亡。值得注意的是，Vγ9Vδ2 T细胞对维奈托克耐药的OCI-AML3细胞系仍保持强效细胞毒性，且在维奈托克存在时活性不受影响。在侵袭性Molm-13细胞系和维奈托克耐药OCI-AML3细胞系构建的两种AML异种移植模型中，Vγ9Vδ2 T细胞治疗均显著延长了小鼠生存期，且在后者模型中观察到与维奈托克的协同效应。 结论：本研究证实Vγ9Vδ2 T细胞可作为AML患者（特别是维奈托克耐药患者）极具潜力的"即用型"免疫治疗策略。
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