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Cell Death Discovery

Cell Death Discovery

IF: 6.09
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Systemic tumor regression with synergy therapy: radiotherapy and CAR-T

Published:22 November 2024 DOI: 10.1038/s41420-024-02245-3 PMID: 39578426
Ma, Xingyu, Zhang, Wei, Zeng, Miao, Asavasupreechar, Teeranut, Kang, Synat, Li, Yisheng, Yu, Li

Abstract

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.

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