Responsiveness to immune checkpoint inhibitors is associated with specific blood T cell clusters and high T cell repertoire richness and diversity in microsatellite stable and instable prostate cancer
While prostate cancer patients with microsatellite instability (MSI) are considered responsive to immune checkpoint blockade (ICB), it remains unclear whether subsets of patients with microsatellite stable (MSS) tumors may derive similar benefit from this approach. Here, we explored immune signatures in a cohort of patients with MSS and MSI metastatic castration-resistant prostate cancer (mCRPC) that were treated with ICB. We reasoned that MSS tumors with immune signatures resembling those of MSI tumors could be a subset with increased sensitivity to ICB. Next-generation T cell repertoire sequencing revealed overlaps between blood and tumor T cells and considerably higher blood T cell richness and diversity in MSI versus MSS cases. This potentially reflects a greater neoepitope load triggering T cell responses in this subset. Interestingly, MSS mCRPC cases with high peripheral blood T cell richness and diversity, but especially MSI-like T cell clusters showed significantly better outcomes on ICB. Taken together, the MSI prostate cancer 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 immunologically similar MSS tumors that may have an increased likelihood to respond to ICB or combinatorial approaches including ICB.