SPOP and MMR/MSI alterations in prostate cancer: relationship with PD-L1, TILs and AR expression

Objective: Despite the promising introduction of anti-PD-L1 therapy for advanced stage of prostate cancer (PCa), recent studies have demonstrated limited success, suggesting the need to improve patient selection. Methods: We retrospectively selected 153 PCa patients. We performed SPOP mutational analysis and evaluated PD-L1 expression, MMR/MSI status, TIL (as CD4/CD8 ratio), and the mRNA expression of AR and CD274. Using SPOP interfering-RNA in two PCa cell lines (LNCaP, PC3) and western-blot analysis, we examined the role of SPOP silencing on CD274 expression. Results: Functionally altered SPOP mutations (14 out of 153 samples, 9.15%) and MMR/MSI status (3.3%) were associated with higher PD-L1 expression (both p < 0.0001), lower TIL (p < 0.0001 and p = 0.0004), and higher Gleason scores (both p < 0.05). SPOP-mutated patients exhibited significantly higher CD274, and AR mRNA expression compared to those without mutations (p = 0.0006 and p = 0.0148). Reducing SPOP expression in cancer cell lines resulted in a significant upregulation of PD-L1 expression. Conclusions: Our analysis identifies SPOP mutations and MMR/MSI status as cofactors in high PD-L1 expression and CD8/TIL presence in PCa, representing potential markers for selecting patients who are more likely to respond immunotherapy or to combined treatment.