Immune checkpoint inhibitors in combination with targeted therapy is improving the response rates of advanced or metastatic renal cancer patients. However, many treated patients either do not respond or develop resistance to therapy, making novel immune checkpoint-based immunotherapies of potential clinical benefit for specific groups of patients.
B7-H3 mRNA and protein expression has been evaluated in human renal cancer cell lines by quantitative PCR and immunoblot, and in vitro functional assays were performed upon B7-H3 knockdown. B7-H3 protein immunostaining has been performed by immunohistochemistry on tissue microarray samples from two distinct renal cancer cohorts, and clinical correlations have been explored. The immune exhaustion gene expression profile has been obtained from a panel of renal cancer whole tissue sections.
B7-H3 is highly expressed in renal cancer cells and knocking down its expression resulted in lower cell viability. In a first cohort of 129 renal cancer specimens, including 96 clear cell renal cell carcinomas (CCRCC), 17 chromophobe renal cell carcinomas (ChRCC), and 16 papillary renal cell carcinomas (PRCC), we explored the correlations between B7-H3 and pathological parameters. B7-H3 was highly expressed in tumor cells from 40% of samples, which correlated with poor outcome and overall survival (OS). In a second cohort of 52 metastatic CCRCC (mCCRCC) patients, approximately half of primary tumors expressed B7-H3 at the primary site, whereas 30% of the metastatic tumors were positive for B7-H3 expression. B7-H3 expression in primary tumors correlated with tumor necrosis, sarcomatoid transformation, disease-free survival, and synchronous metastasis, while B7-H3 expression in metastasis was correlated to metastases to the lymph nodes. Molecular analysis revealed correlation between B7-H3 expression and leukocyte-specific gene expression profiles and signaling pathways implicated in immune exhaustion in renal cancer samples.
Together, our findings suggest a role for B7-H3 in renal cancer immune exhaustion and highlight B7-H3 as an actionable novel immune checkpoint protein in advanced and metastatic renal cancer.
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Asociación Instituto de Investigación Sanitaria Biocruces Bizkaia.
CENX is the recipient of a Miguel Servet Research contract (Type I) from Instituto de Salud Carlos III (ISCIII) (CP20/00008) co-financed by European Social Fund+. This work was funded by ISCIII (Spain and European Social Fund+, grant number CP20/0008) and Stiftelsen til fremme av forskning innen nyresykdommer/The Foundation for the Promotion of Research in Kidney Diseases (Unifor 2019 and 2021) to CENX; and by the Ministerio de Economía y Competitividad (Spain and Fondo Europeo de Desarrollo Regional, grant number SAF2016-79847-R) to RP and JIL.
All authors have declared no conflicts of interest.