Gender-specific Stratification of Survival Following Immune Checkpoint Inhibitor Therapy Based on Intratumoral Expression of a B cell Gene Signature

BACKGROUND: There is a great need to identify biomarkers that can accurately identify patients who will obtain the most clinical benefit from immune checkpoint inhibitor (ICI) therapy. While high intratumoral B cell gene expression correlated with an ICI response in melanoma, whether it adds predictive value in other cancers is unknown. OBJECTIVE: To examine the relationship between B cell gene signature (BCGS) expression and overall survival (OS) following ICI treatment. DESIGN, SETTING, AND PARTICIPANTS: A total of 348 patients with advanced urothelial carcinoma from the IMvigor 210 phase 2 clinical trial of atezolizumab and 406 patients with muscle-invasive bladder cancer from The Cancer Genome Atlas (TCGA) were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed tumor RNA sequencing data of included patients to examine the relationships between a BCGS and clinical outcomes. RESULTS AND LIMITATIONS: Tumors with high levels of B cell and CD8+ T cell gene signatures (BCGS/CD8TGS or B8T high/high) were associated with the longest OS of all B8T groups. Moreover, the B8T cell signature stratified patients whose tumors had a high tumor mutational burden or high programmed death ligand 1 (PD-L1) into subsets with differential OS outcomes. Whereas the B8T high/high tumors were associated with the best clinical outcomes in ICI-treated men, they were not associated with better OS in women. Conversely, women with B8T high/high tumors had the best clinical outcomes in non-ICI-treated muscle-invasive bladder cancer. CONCLUSIONS: These data suggest that the B8T signature can enhance OS stratification in patients with advanced urothelial carcinoma who are treated with ICI therapy and that sex-specific differences in the tumor immune microenvironment may drive disparate outcomes. PATIENT SUMMARY: We examined whether the presence of two immune cell gene signatures within tumor samples impact survival in patients with bladder cancer. High levels of both of these signatures (B cells and CD8+ T cells) associate with superior survival in patients who receive immune therapy.