State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
Mol Ther. 2023 Nov 1;31(11):3193-3209. doi: 10.1016/j.ymthe.2023.09.010. Epub 2023 Sep 20.
Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR-T) cells displayed limited efficacy in CLDN18.2-positive pancreatic ductal adenocarcinoma (PDAC). Strategies are needed to improve the trafficking capacity of CLDN18.2-specific CAR-T cells. PDAC has a unique microenvironment that consists of abundant cancer-associated fibroblasts (CAFs), which could secrete stromal cell-derived factor 1α (SDF-1α), the ligand of CXCR4. Then, we constructed and explored CLDN18.2-targeted CAR-T cells with CXCR4 co-expression in treating immunocompetent mouse models of PDAC. The results indicated that CXCR4 could promote the infiltration of CAR-T cells and enhance their efficacy in vivo. Mechanistically, the activation of signal transducer and activator of transcription 3 (STAT3) signaling was impaired in CXCR4 CAR-T cells, which reduced the release of inflammatory factors, such as tumor necrosis factor-α, IL-6, and IL-17A. Then, the lower release of inflammatory factors suppressed SDF-1α secretion in CAFs via the nuclear factor κB (NF-κB) pathway. Therefore, the decreased secretion of SDF-1α in feedback decreased the migration of myeloid-derived suppressor cells (MDSCs) in tumor sites. Overall, our study demonstrated that CXCR4 CAR-T cells could traffic more into tumor sites and also suppress MDSC migration via the STAT3/NF-κB/SDF-1α axis to obtain better efficacy in treating CLDN18.2-positive pancreatic cancer. Our findings provide a theoretical rationale for CXCR4 CAR-T cell therapy in PDAC.
CLDN18.2（CLDN18.2）-特异性嵌合抗原受体（CAR-T）细胞在 CLDN18.2 阳性胰腺导管腺癌（PDAC）中的疗效有限。需要采取策略来提高 CLDN18.2 特异性 CAR-T 细胞的迁移能力。PDAC 具有独特的微环境，其中包含丰富的癌相关成纤维细胞（CAF），这些细胞可以分泌基质细胞衍生因子 1α（SDF-1α），即 CXCR4 的配体。然后，我们构建并探索了在免疫功能正常的 PDAC 小鼠模型中治疗用的 CLDN18.2 靶向 CAR-T 细胞，该细胞表达 CXCR4。结果表明，CXCR4 可以促进 CAR-T 细胞的浸润，并增强其体内疗效。从机制上讲，CXCR4 CAR-T 细胞中信号转导和转录激活因子 3（STAT3）信号的激活受到损害，这减少了炎性因子的释放，例如肿瘤坏死因子-α、IL-6 和 IL-17A。然后，较低水平的炎性因子通过核因子 κB（NF-κB）途径抑制 CAF 中 SDF-1α 的分泌。因此，反馈作用下 SDF-1α 的分泌减少降低了肿瘤部位髓源性抑制细胞（MDSC）的迁移。总的来说，我们的研究表明，CXCR4 CAR-T 细胞可以更多地迁移到肿瘤部位，并通过 STAT3/NF-κB/SDF-1α 轴抑制 MDSC 迁移，从而在治疗 CLDN18.2 阳性胰腺癌中获得更好的疗效。我们的研究结果为 CXCR4 CAR-T 细胞疗法治疗 PDAC 提供了理论依据。
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