ArticleThe journal of pathology. Clinical research2026
Immune checkpoint profiling of B7-H proteins predicts survival and treatment response in metastatic clear cell renal cell carcinoma.
Article in The journal of pathology. Clinical research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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