免疫疗法
肿瘤微环境
癌症研究
CD8型
T细胞
趋化因子
免疫系统
细胞毒性T细胞
免疫学
膀胱癌
癌症免疫疗法
医学
癌症
生物
体外
内科学
生物化学
作者
Anze Yu,Jiao Hu,Liangmin Fu,Gaowei Huang,Dingshan Deng,Mingxiao Zhang,Yinghan Wang,Guannan Shu,Lanyu Jing,Huihuang Li,Xu Chen,Taowei Yang,Jinhuan Wei,Zhenhua Chen,Xiongbing Zu,Junhang Luo
标识
DOI:10.1136/jitc-2023-007230
摘要
Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing protein (LRFN) family has previously been implicated in regulating brain dysfunction; however, the mechanisms underlying the effect of LRFN2 on the tumor microenvironment (TME) and immunotherapy remain unclear.Here we combined bulk RNA sequencing, single-cell RNA sequencing, ProcartaPlex multiple immunoassays, functional experiments, and TissueFAXS panoramic tissue quantification assays to demonstrate that LRFN2 shapes a non-inflammatory TME in BLCA.First, comprehensive multiomics analysis identified LRFN2 as a novel immunosuppressive target specific to BLCA. We found that tumor-intrinsic LRFN2 inhibited the recruitment and functional transition of CD8+ T cells by reducing the secretion of pro-inflammatory cytokines and chemokines, and this mechanism was verified in vitro and in vivo. LRFN2 restrained antitumor immunity by inhibiting the infiltration, proliferation, and differentiation of CD8+ T cells in vitro. Furthermore, a spatial exclusivity relationship was observed between LRFN2+ tumor cells and CD8+ T cells and cell markers programmed cell death-1 (PD-1) and T cell factor 1 (TCF-1). Preclinically, LRFN2 knockdown significantly enhanced the efficacy of ICI therapy. Clinically, LRFN2 can predict immunotherapy responses in real-world and public immunotherapy cohorts. Our results reveal a new role for LRFN2 in tumor immune evasion by regulating chemokine secretion and inhibiting CD8+ T-cell recruitment and functional transition.Thus, LRFN2 represents a new target that can be combined with ICIs to provide a potential treatment option for BLCA.
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