新型CML特异性Dex无细胞疫苗增强NK/T细胞抗CML作用的研究

Chronic myeloid leukemia (CML) is a malignant tumor that originates from hematopoietic stem cells. Imatinib, as the first-line treatment of CML, is susceptible to drug resistance and cannot completely cure CML. In addition, CD8+ T cell-mediated adaptive immunity and NK/T cell-mediated innate immunity are impaired in CML patients，thus it is a great challenge to treat CML patients by immunotherapy. Therefore, there is a need to explore new CML treatment strategies. DC-derived exosome (Dex)-based immunotherapy has demonstrated good anti-tumor efficacy and therapeutic prospects. However, the use of CML specific Dex for CML therapy has not been reported. Our previous unpublished data indicate that specific DC cells loaded with BCR-ABL antigen can stimulate the production of BCR-ABL-specific cytotoxic T lymphocytes responses. This project proposes a new idea for killing CML cells of activating non-MHC-restricted cytotoxicity of NK/T cells by overexpressing MICA in a specific Dex loaded with BCR-ABL antigen. The project will investigate the activation of NK/T cells by this exosome in vitro and the immune effect in CML model mice. The implementation of this project is expected to provide a new type of exosome-based cell-free vaccine therapy for CML patients.

慢性髓细胞白血病(CML)是一种起源于造血干细胞的恶性增殖性肿瘤。一线用药伊马替尼具有易产生耐药性、不能根治CML等缺陷。另外，CML患者中CD8+T细胞介导的适应性免疫和NK/T细胞介导的固有免疫都受损，通过免疫疗法来治疗CML患者面临很大挑战。因此需要探索新的CML治疗策略。基于树突状细胞来源外泌体(Dex)的免疫疗法展现出好的抗肿瘤疗效和治疗前景。然而将CML特异性Dex用于CML治疗未见报道。我们前期未发表的数据表明负载BCR-ABL抗原的特异性DC细胞能刺激产生CML特异性细胞毒性T细胞应答。本项目提出，在负载BCR-ABL抗原的特异性Dex中过表达MICA，同时激活NK细胞和T细胞介导的非MHC限制性细胞毒作用进而杀伤CML细胞的新思路。探讨该Dex在体外对NK/T细胞的活化作用并观察其在CML模型鼠体内的免疫效应。本项目的实施有望为CML患者提供一种新型外泌体无细胞疫苗。

酪氨酸激酶抑制剂在治疗慢性髓细胞白血病（CML）方面取得了惊人的进展，但与T315I突变相关的进展和耐药性仍然是疾病治疗的主要障碍。负载抗原的树突状细胞来源的外泌体（Dex）可诱导NK细胞激活，但目前尚未取得满意的临床疗效。迫切需要寻找一种免疫治法能同时激活NK细胞和T细胞，使其发挥更有效的抗肿瘤作用。视黄酸早期诱导物-1γ（RAE-1γ）是自然杀伤细胞群2成员D（NKG2D）的主要配体，在NK细胞和T淋巴细胞反应中起重要作用。在本研究中，我们从小鼠树突状细胞（DC）中生成富含RAE-1γ分子的CML特异性Dex （CML-RAE-1γ-Dex），该Dex能够通过NKG2D-NKG2D配体途径同时激活T细胞和NK细胞，从而在体内外诱导出更强的抗CML效果。同样，在T315I突变的CML细胞中也观察到有效的免疫反应。这些数据表明，CML-RAE-1γ-Dex疫苗可能是CML患者，特别是T315I突变患者的一种有前途的治疗策略。