ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation
Wentao Zhang, Wen Ren, Shuyan Guo, Hu Han, Wei‐Wen Cai, Haowen Bai, Long Li, Xiangyan Jiang, Xin Zheng, Tiansheng Zhang, Yan Wang, Huili Ye, Hongtai Cao, Wengui Shi, Huinian Zhou, Zeyuan Yu, Long Qin, Zuoyi Jiao
Abstract
Gastric cancer (GC) is characterised by a dense stromal microenvironment, lack of therapeutic targets, and limited effective treatment options, collectively leading to a poor prognosis. Here, we identify UL16 binding protein 2 (ULBP2) as a potential therapeutic target in GC. Mechanistically, ULBP2 overexpression activates the TGF-β signalling pathway, promoting the activation of cancer-associated fibroblasts (CAFs) and tumor progression in GC. Furthermore, we developed ULBP2 CAR-T cells and assessed their therapeutic potential in GC cell lines, organoids, cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. We showed that ULBP2 CAR-T cells effectively eliminated GC cell lines and organoids and, either alone or in combination with an anti-PD-1 antibody, significantly inhibited tumor growth and prolonged survival in both CDX and PDX mouse models. In conclusion, ULBP2 contributes to GC progression by promoting TGF-β mediated CAF activation, which collectively reinforce the dense stromal microenvironment. Targeting ULBP2 suppresses tumor growth, reduces stromal deposition, and promotes T cell infiltration, thereby enhancing the efficacy of immunotherapy in GC.