High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition.

Various immune signatures predictive of resistance to immune checkpoint inhibitors (ICI) have been described in multiple solid cancers, but still under-investigated in gynecological (GYN) cancer. For 49 GYN cancer patients included in our study, without transcriptome signature, immune-related toxicity was the only clinical predictor of ICI treatment response (p = 0.008). The objective clinical response was the only predictor of progression-free survival (ICI-PFS, p = 0.0008) and overall survival (ICI-OS, p = 0.01). Commonly used ICI marker PD-L1 expression negatively correlated with progression-free survival (ICI-PFS) (p = 0.0019). We performed transcriptome and signaling pathway enrichment analyses based on ICI treatment responses and the survival outcome, and further estimated immune cell abundance using 547 gene markers. Our data revealed that TGF-β regulated signaling pathway was noted to play an important role in immunotherapy failure. Using our 6-genes TGF-β score, we observed longer ICI-PFS associated with lower TGF-β score (8.1 vs. 2.8 months, p = 0.046), which was especially more prominent in ovarian cancer (ICI-PFS 16.6 vs. 2.65 months, p = 0.0012). Further, abundant immunosuppressive cells like T-regulatory cells, eosinophils, and M2 macrophages were associated with shorter ICI-OS and correlated positively with CD274 and CTLA4 expressions. This study provides insight on the potential role of TGF-β in mediating immunotherapy resistance and cross-talking to immunosuppressive environment in GYN cancer. The TGF-β score, if validated in a larger cohort, can identify patients who likely to fail ICI and benefit from targeting this pathway to enhance the response to ICI.