Immune checkpoint profiling of B7-H proteins predicts survival and treatment response in metastatic clear cell renal cell carcinoma.

The B7-H family of immune checkpoint proteins plays a central role in tumor immune regulation, yet their prognostic and predictive significance in metastatic clear cell renal cell carcinoma (ccRCC) remains incompletely defined. We analyzed a retrospective cohort of primary tumor specimens from 145 patients with synchronous or metachronous metastatic ccRCC to evaluate the expression of B7-H3, B7-H4, B7-H5, and B7-H7 and their association with tumor aggressiveness, treatment response, and long-term survival. Immunohistochemistry revealed marked intratumoral heterogeneity and distinct compartmentalized expression patterns, with B7-H3 detected in both tumor cells and stromal compartments, B7-H4 exclusively expressed in tumor cells, B7-H5 localized to tumor cells and tumor-infiltrating lymphocytes (TILs), and B7-H7 detected in both tumor cells and TILs. We did not detect any overlap in expression between B7-H proteins and PD-L1 positivity in TILs. High B7-H3 expression in tumor and stroma was significantly associated with higher histological grade, increased local invasion, lymph node involvement, and advanced stage. B7-H5 expression in TILs correlated with impaired Eastern Cooperative Oncology Group performance status. Elevated B7-H3 predicted unfavorable response to tyrosine kinase inhibitors, mechanistic target of rapamycin inhibitors, and immune checkpoint inhibitors, whereas B7-H5 negativity in tumor cells associated with more favorable treatment outcomes. B7-H4 and B7-H7 expression in tumor cells were associated with features of tumor aggressiveness and immune suppression, further highlighting the potential role of multiple B7-H family checkpoints in metastatic ccRCC. In multivariable Cox regression models, B7-H3 expression in tumor and stroma independently predicted shorter disease-free and overall survival. B7-H5 expression in TILs independently predicted reduced overall survival. These findings identify B7-H3 as a robust biomarker of tumor aggressiveness, therapeutic resistance, and adverse prognosis in metastatic ccRCC, while B7-H5 in TILs provides complementary prognostic information. Integrated profiling of B7-H immune checkpoints in primary tumors may refine clinical risk stratification and support the development of biomarker-guided immunotherapeutic strategies.