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

bjective. 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.