肿瘤细胞治疗研究
英文原题：Modified dendritic cell-derived exosomes activate both NK cells and T cells through the NKG2D/NKG2D-L pathway to kill CML cells with or without T315I mutation.
这种基于 CML-RAE-1-Dex 疫苗的方法可能是 CML 治疗的一种有前景的策略，尤其对于携带 T315I 突变的病例。
背景：酪氨酸激酶抑制剂显著推动了慢性髓系白血病（CML）的治疗进展，但疾病进展及与 T315I 突变相关的药物耐药仍是主要障碍。树突状细胞来源外泌体（Dex）可诱导 NK 细胞免疫，但尚未取得满意的临床疗效。亟需通过同时诱导 NK 细胞和 T 细胞活化来增强抗肿瘤免疫。视黄酸早期诱导蛋白 1（RAE-1）是NK 细胞组 2 成员 D（NKG2D）的主要配体，在 NK 细胞和 T 淋巴细胞应答中发挥重要作用。我们使用表达 RAE-1 的 CML 细胞或 T315I 突变 CML 细胞裂解物负载树突状细胞（DC），制备富含 RAE-1 的 CML 特异性 Dex（CML-RAE-1-Dex），旨在同时激活 NK 细胞和 T 淋巴细胞。 方法：制备新型 CML-RAE-1-Dex 疫苗，表达 RAE-1 并负载 CML 肿瘤细胞裂解物。将 NK 细胞或 T 淋巴细胞与疫苗共孵育，通过流式细胞术评估免疫细胞活化和增殖；采用 ELISPOT、ELISA 和 LDH 检测细胞因子生成，以及对携带或不携带 T315I 突变的 CML 细胞的细胞毒作用。使用 BCR-ABL 或 BCR-ABL T315I 诱导的 CML 模型评估 Dex 的体内免疫功能。 结果：成功制备 CML-RAE-1-Dex。其有效增强 NK 细胞、CD4⁺ T 细胞和 CD8⁺ T 细胞的增殖与效应功能，并在体外产生强效抗 CML 活性。此外，基于 CML-RAE-1-Dex 的免疫治疗可抑制 CML 小鼠模型中的白血病发生，并产生持久免疫记忆。对于携带 T315I 突变的伊马替尼耐药 CML 细胞，也观察到类似免疫反应。 结论：基于 CML-RAE-1-Dex 疫苗的策略可能成为 CML 治疗的有前景方法，尤其适用于 T315I 突变病例。
BACKGROUND: Tyrosine kinase inhibitors have achieved quite spectacular advances in the treatment of chronic myeloid leukemia (CML), but disease progression and drug resistance that related to the T315I mutation, remain major obstacles. Dendritic cell-derived exosomes (Dex) induce NK cell immunity, but have yet to achieve satisfactory clinical efficacy. An approach to potentiate antitumor immunity by inducing both NK- and T-cell activation is urgently needed. Retinoic acid early inducible-1 (RAE-1 ), a major ligand of natural killer group 2 member D (NKG2D), plays an important role in NK-cell and T-lymphocyte responses. We generated RAE-1 enriched CML-specific Dex (CML-RAE-1 -Dex) from dendritic cells (DCs) pulsed with lysates of RAE-1 -expressing CML cells or T315I-mutant CML cells, aiming to simultaneously activate NK cells and T lymphocytes. METHODS: We generated novel CML-RAE-1 -Dex vaccines, which expressed RAE-1 , and were loaded with CML tumor cell lysates. NK cells or T lymphocytes were coincubated with CML-RAE-1 -Dex vaccines. Flow cytometry was performed to evaluate the activation and proliferation of these immune cells. Cytokine production and cytotoxicity toward CML cells with or without the T315I mutation were detected by ELISPOT, ELISA and LDH assays. CML models induced by BCR-ABL or BCR-ABL T315I were used to determine the immunological function of Dex in vivo. RESULTS: Herein, CML-RAE-1 -Dex were prepared. CML-RAE-1 -Dex effectively enhanced the proliferation and effector functions of NK cells, CD4 + T cells and CD8 + T cells, which in turn produced strong anti-CML efficacy in vitro. Moreover, CML-RAE-1 -Dex-based immunotherapy inhibited leukemogenesis and generated durable immunological memory in CML mouse models. Similar immune responses were also observed with imatinib-resistant CML cells carrying the T315I mutation. CONCLUSIONS: This approach based on CML-RAE-1 -Dex vaccines may be a promising strategy for CML treatment, especially for cases with the T315I mutation.
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