Case of Complete Response to Immunotherapy in MMR-Deficient Prostate Cancer Associated with NK-like and CD4+CD8+ T-cells

Mismatch repair deficiency (dMMR) and microsatellite instability (MSI-H) are rare in prostate cancer, occurring in 2-4% of cases. These defects result in increased genomic instability and elevated tumor mutational burden (TMB), which can support responses to immune checkpoint inhibitors (ICIs). Here, we report a patient with locally-advanced Gleason 5+5=10 prostatic adenocarcinoma harboring MSH2 and MSH6 genomic deletions with ultrahigh TMB (>250 mutations/megabase) in whom pembrolizumab resulted in a striking complete radiographic, pathologic, and molecular response. Using digital-spatial microscopy, single-cell RNA/TCR-sequencing, and multiplex cytometry, we identify atypical tumor-infiltrating T-cells with natural killer-like phenotypes and CD4+CD8+ (double-positive) lymphocytes. These unique and clonal T-cell populations expand preferentially following ICI and adopt terminally-differentiated and cytotoxic profiles that may drive clinical response. Similar T-cells are also present in diverse cancers and expand exclusively in ICI-responsive patients. These findings inform on cellular mechanisms by which immunotherapies may mediate profound responses in patients with dMMR solid tumors.