IGFBP7 and the Tumor Immune Landscape: A Novel Target for Immunotherapy in Bladder Cancer

Frontiers in Immunology

Peng Ge²  Xianyanling Yi³  Tianyi Zhang³  Hong Li³  Xiaonan Zheng³  Dazhou Liao³  Jianzhong Ai³  Jin Li³  Hang Xu³  Xiaoyan Lyu⁴ 

[1] Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China;Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China;Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China;Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China;

关键词: IFGBP7;    bladder cancer;    immunotherapy;    tumor microenvironment;    molecular subtype;    hypoxia;   

DOI  :  10.3389/fimmu.2022.898493

来源: DOAJ

【 摘 要 】

Insulin-like growth factor binding protein-7 (IGFBP7) was recently reported to be a ligand of CD93, a potential target to normalize vasculature and attenuate immunotherapy. However, its role in the tumor microenvironment (TME) and immunotherapy response of bladder cancer (BLCA) remains unclear. We comprehensively evaluated the correlation between IGFBP7 and multiple immunological characteristics of BLCA across The Cancer Genome Atlas (TCGA) and two external cohorts. Importantly, the response of IGFBP7-grouped BLCA patients to immunotherapy was predicted and validated by five real-word immunotherapy cohorts. Finally, we developed an IGFBP7-based immune risk model validated by five independent cohorts. IGFBP7 modulated the TME across pan-caners. In BLCA, high expression of IGFBP7 was correlated with more aggressive clinical features. IGFBP7 was positively associated with immunomodulators and promoted tumor-infiltrating lymphocyte trafficking into the tumor microenvironment. However, T cells recognition and tumor cell killing were lower in the high-IGFBP7 group. In addition, high expression of IGFBP7 displayed lower enrichment scores for most pro-immunotherapy pathways. Clinical data from IMvigor210 and GSE176307 indicated that IGFBP7 negatively correlated with the BLCA immunotherapy response. The same trend was also observed in a renal cell carcinoma (RCC) cohort and two melanoma cohorts. Notably, urothelial and luminal differentiation were less frequently observed in the high-IGFBP7 group, while neuroendocrine differentiation was more frequently observed. Mechanistically, high IGFBP7 was associated with an enriched hypoxia pathway and higher expression of key genes in ERBB therapy and antiangiogenic therapy. Furthermore, our IGFBP7-based immune risk model was able to predict the prognosis and response to immunotherapy with good accuracy (5-year AUC = 0.734). Overall, IGFBP7 plays a critical role in the immunoregulation and TME of BLCA and may serve as a novel potential target for combination treatment with immunotherapy for BLCA.

【 授权许可】

Unknown