Ma Xingyu, Zhang Wei, Zeng Miao, Asavasupreechar Teeranut, Kang Synat, Li Yisheng, Yu Li
Department of Hematology and Oncology, Shenzhen University General Hospital, International Cancer Center, Hematology Institution of Shenzhen University, Shenzhen University Health Science Center, Shenzhen Clinical Research Center for hematologic disease, Shenzhen University, Shenzhen, China.
Biomedical Laboratory, Shenzhen University-Haoshi Cell Therapy Institute, Shenzhen, China.
Cell Death Discov. 2024 Nov 22;10(1):479. doi: 10.1038/s41420-024-02245-3.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most poorly prognostic digestive tract malignancies. CLDN18.2 CAR-T therapy has recently shown promising clinical effects in PDAC. Radiotherapy, a traditional treatment, can induce systemic immune activation and abscopal effects. However, the synergistic effect and mechanism of their combination in PDAC treatment remain poorly understood. In this study, we developed a CLDN18.2-specific CAR-T and applied it to unilateral and bilateral mouse tumor models. Our results demonstrated that this synergy therapy not only improved tumor-killing effects in unilateral tumor-bearing mice but also induced regression in both local and distant tumors in bilateral tumor models. Mechanistically, early radiation-induced apoptosis promoted the proliferation of CD8 + T cells, while increased chemokine CCL2 levels from localized and distant tumor sites facilitated CAR-T and endogenous T cell infiltration, leading to systemic tumor suppression. This study proposes a promising approach for treating metastatic pancreatic cancer by combining radiotherapy and CAR-T therapy, elucidating the mechanism of CAR-T cell-enhanced radiotherapy effects ex vivo, and highlighting a novel strategy for combating metastatic pancreatic cancer.
胰腺导管腺癌（PDAC）是预后最差的消化道恶性肿瘤之一。CLDN18.2嵌合抗原受体T细胞（CAR-T）疗法最近在PDAC中显示出了有前景的临床效果。放疗作为一种传统治疗方法，可诱导全身免疫激活和远隔效应。然而，它们在PDAC治疗中的协同作用及机制仍知之甚少。在本研究中，我们构建了一种CLDN18.2特异性CAR-T，并将其应用于单侧和双侧小鼠肿瘤模型。我们的结果表明，这种联合疗法不仅提高了单侧荷瘤小鼠的肿瘤杀伤效果，还在双侧肿瘤模型中诱导了局部和远处肿瘤的消退。机制上，早期放疗诱导的凋亡促进了CD8 + T细胞的增殖，而局部和远处肿瘤部位趋化因子CCL2水平的升高促进了CAR-T和内源性T细胞的浸润，从而导致全身肿瘤抑制。本研究提出了一种通过放疗与CAR-T疗法联合治疗转移性胰腺癌的有前景的方法，阐明了CAR-T细胞增强放疗效果的体外机制，并突出了一种对抗转移性胰腺癌的新策略。
