Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice
Olaparib Suppresses MDSC Recruitment via SDF1α/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice
复制标题
Olaparib 通过 SDF1α/CXCR4 轴抑制 MDSC 募集，提高 CAR-T 细胞对小鼠乳腺癌的抗肿瘤功效。
DOI：
10.1016/j.ymthe.2020.09.034
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发表时间：
2021-01-06
影响因子：
12.4
通讯作者：
Li, Zonghai
中科院分区：
文献类型：
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作者：
Sun, Ruixin;Luo, Hong;Li, Zonghai
恶劣的肿瘤微环境是嵌合抗原受体修饰T（CAR-T）细胞功效的主要障碍之一，联合治疗可能是克服这一障碍的潜在方法。聚（ADP-核糖）聚合酶抑制剂（PARPi）在乳腺癌方面已显示出巨大的潜力。在这项研究中，我们探索了 PAPRi olaparib 与 EGFRvIII 靶向 CAR (806-28Z CAR) T 细胞在免疫功能正常的乳腺癌小鼠模型中的可能组合。结果表明，给予奥拉帕尼可以显着增强806-28Z CAR-T细胞的体内功效。有趣的是，我们观察到奥拉帕尼可以抑制骨髓源性抑制细胞（MDSC）迁移并促进肿瘤组织中CD8（+）T细胞的存活。从机制上讲，奥拉帕尼可减少癌症相关成纤维细胞 (CAF) 释放的 SDF1 α 表达，从而减少 MDSC 通过 CXCR4 的迁移。综上所述，这项研究证明奥拉帕尼至少部分通过 SDF1 α/CXCR4 轴抑制 MDSC 迁移来增强 CAR-T 细胞疗法的抗肿瘤活性。这些发现揭示了 PARPi 功能的新机制，并为 PARPi 与 CAR-T 细胞联合治疗乳腺癌提供了额外的机制原理。
A hostile tumor microenvironment is one of the major obstacles for the efficacy of chimeric antigen receptor modified T (CAR-T) cells, and combination treatment might be a potential way to overcome this obstacle. Poly(ADP-ribose) polymerase inhibitor (PARPi) has demonstrated tremendous potential in breast cancer. In this study, we explored the possible combination of the PAPRi olaparib with EGFRvIII-targeted CAR (806-28Z CAR) T cells in immunocompetent mouse models of breast cancer. The results indicated that the administration of olaparib could significantly enhance the efficacy of 806-28Z CAR-T cells in vivo. Interestingly, we observed that olaparib could suppress myeloid-derived suppressor cell (MDSC) migration and promote the survival of CD8(+) T cells in tumor tissue. Mechanistically, olaparib was shown to reduce the expression of SDF1 alpha released from cancer-associated fibroblasts (CAFs) and thereby decreased MDSC migration through CXCR4. Taken together, this study demonstrated that olaparib could increase the antitumor activities of CAR-T cell therapy at least partially through inhibiting MDSC migration via the SDF1 alpha/CXCR4 axis. These findings uncover a novel mechanism of PARPi function and provide additional mechanistic rationale for combining PARPi with CAR-T cells for the treatment of breast cancer.