Prostate tumor immune microenvironment changes following immunotherapy shared by patients who developed anti-tumor...

Checkpoint inhibitors targeting PD-1/PD-L1 have revolutionized cancer immunotherapy, yet their efficacy in prostate cancer has been limited. We previously reported a clinical trial (NCT02499835) evaluating PD-1 blockade combined with an anti-tumor DNA vaccine, pTVG-HP (encoding prostatic acid phosphatase), in patients with metastatic castration-resistant prostate cancer. Decreases in serum prostate-specific antigen (PSA) levels were observed in 35% of patients, and 42% of patients developed immune-related adverse events (irAE). In long-term follow-up, any decrease in PSA or the development of an irAE was associated with prolonged overall survival (p = 0.009 or p = 0.006, respectively), suggesting a potential association between irAE and anti-tumor immunity. To evaluate this, tumor biopsies obtained pre- and post-treatment from 12 patients were evaluated by gene expression profiling and spatial protein analysis. Clinical responders (those with any decrease in PSA) presented with reduced checkpoint marker expression and increased expression of markers associated with dendritic cells, antigen presentation, and T-cell activation. These gene expression signatures highly overlapped with signatures from patients who experienced an irAE. Conversely, non-responders showed enrichment of immunosuppressive pathways, including elevated expression of VISTA and myeloid-derived suppressor cell (MDSC)-associated markers. Patients without irAE had increased expression of PARP. These findings suggest that patients experiencing irAEs can have immune responses to tumor irrespective of obvious anti-tumor efficacy, at least with these treatments, and underscore the importance of tumor-infiltrating professional antigen presenting cells and T-cell activation for successful immunotherapy. Moreover, our findings suggest that combining vaccines and PD-1 blockade with MDSC-targeting therapies, anti-VISTA, and/or anti-PARP therapies might be further explored.