XCL1-secreting CEA CAR-T cells enhance endogenous CD8 + T cell responses to tumor neoantigens to confer a long-term antitumor immunity

作者：X. Li, Feifei Wang, Kun Chen, Zhiyuan Wu, Ruochan Zhang, Chentong Xiao, Fei Zhao, Dongmei Wang, Hong Zhao, Yuliang Ran, Chunfeng Qu · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2025 · DOI：10.1136/jitc-2024-010581 · 被引用次数：18 · 研究领域：CAR-T cell therapy research、Immunotherapy and Immune Responses、Cutaneous lymphoproliferative disorders research

Background Therapeutic efficacy of carcinoembryonic antigen (CEA)-specific chimeric antigen receptor (CAR) T cells against colorectal cancer (CRC) remains limited due to the unique characteristics and distinct microenvironments of tumor tissues. We modified CEA-specific CAR-T cells, aiming to stimulate endogenous CD8 + T cell responses against neoantigens that were derived from CEA-positive tumors destroyed by the CAR T cells. Methods In a conventional CEA CAR (reg-CAR), we modified it to express lymphotactin XCL1 and interleukin (IL)-7 genes, constructing a modified 7XCL1-CAR. By generating the CEA-specific 7XCL1-CAR T cells, we assessed their antitumor efficacy against CRC cells with varying levels of CEA expression, both in cell-cultures and in two strains of tumor-bearing syngeneic mice. Results Following retroviral transduction, 7XCL1-CAR T cells and reg-CAR T cells exhibited similar positive proportions of CEA-CAR and CD4:CD8 ratios. In co-culture system with CEA-negative CT26 cells, no differences in cytotoxicity were observed between 7XCL1-CAR and reg-CAR T cells. However, in co-culture with CT26.CEA high and CT26.CEA int cells, 7XCL1-CAR T cells displayed higher cytotoxicity than that reg-CAR T cells after 60 hours. On interaction with CT26.CEA-positive cells, 7XCL1-CAR T cells secreted higher levels of XCL1 and IL-7, effectively recruited the most potent cross-presenting cDC1s (type-I conventional dendritic cells), and sustained the antitumor activity of CAR-T cells...