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.