Responsiveness to immune checkpoint inhibitors is associated with a peripheral blood T cell signature in metastatic castration resistant prostate cancer. Signature of immunotherapy-responsive prostate cancer

PURPOSE: While most patients with microsatellite instable (MSI) metastatic castration-resistant prostate cancer (mCRPC) respond to immune checkpoint blockade (ICB), only a small subset of patients with microsatellite stable (MSS) tumors have similar benefit. Biomarkers defining ICB susceptible subsets of patients with MSS mCRPC are urgently needed. METHODS: Using next-generation T cell repertoire sequencing we explored immune signatures in patients with MSS and MSI mCRPC who were treated with or without ICB. We defined subset-specific immune metrics as well as T cell clusters and correlated the signatures with treatment benefit. RESULTS: Consistent overlaps between tumor and peripheral T cell repertoires suggested that blood was an informative material to identify relevant T cell signatures. We found considerably higher blood T cell richness and diversity and more shared T cell clusters with low generation probability (pGen) in MSI versus MSS mCRPC potentially reflecting more complex T cell responses due to greater neoepitope load in the MSI subset. Interestingly, MSS mCRPC cases with shared low pGen T cell clusters showed significantly better outcomes on ICB, but not on other treatments, compared to patients without such clusters. Blood clearance of T cell clusters upon ICB treatment initiation appeared compatible with T cell migration to the primary tumor or metastatic sites during the process of clonal replacement as described for other tumors on ICB. CONCLUSION: Taken together, the MSI mCRPC subset shows a distinct T cell signature that can be detected in blood. This signature points to immune parameters that could help to identify a subset of patients with MSS mCRPC who may have an increased likelihood to respond to ICB or combinatorial approaches including ICB.