Immune inactivation by CD47 expression predicts clinical outcomes and therapeutic responses in clear cell renal cell carcinoma patients.

Background: CD47 has been identified as a phagocytosis checkpoint conferring poor clinical outcomes in various cancer types. A flurry of clinical trials designed to evaluate agents that block CD47 have been initiated. We aimed to explore the clinical significance of CD47 and its correlation with immune infiltration and molecular features in clear cell renal cell carcinoma (ccRCC).

Methods: 235 tumor tissue microarray specimens of ccRCC patients from Zhongshan Hospital, 530 ccRCC patients from The Cancer Genome Atlas and 726 ccRCC patients from JAVELIN Renal 101 study were analyzed. CD47 expression and immune contexture were examined by immunohistochemistry and CIBERSORT algorithm. Survival analyses were conducted through Kaplan-Meier curves and Cox regression model.

Results: We demonstrated that ccRCC patients with high CD47 expression exhibited inferior overall survival and recurrence-free survival. CD47 expression associated with heavily immune infiltrated but immunosuppressed microenvironment. CD8 T cells infiltration had discordant prognostic value based on CD47 expression, where high CD8 T cell infiltration was associated with worse clinical outcome in CD47 patients and with favorable prognosis in CD47 patients. Patients with mutated PBRM1 and SETD2 correlated with decreased CD47 mRNA expression. Patients with higher CD47 expression possessed improved PFS in ICI + VEGFR TKI combination therapy.

Conclusions: CD47 expression was an independent prognosticator of clinical outcome for ccRCC patients. CD47 expression correlated with ccRCC molecular classification and response to combination therapy. The phagocytosis checkpoint CD47 could be applied as an attractive candidate for immunotherapeutic approach in ccRCC.