Homologous recombination repair deficient prostate cancer represents an immunologically distinct subtype

Abstract

Homologous recombination repair deficiency (HRD) is observed in 10% of patients with castrate-resistant prostate cancer (PCa). Preliminary data suggest that HRD-PCa might be more responsive to immune checkpoint inhibitors (ICIs). In this study, we compare the tumor immune landscape and peripheral T cell receptor (TCR) repertoire of patients with and without HRD-PCa to gain further insight into the immunogenicity of HRD-PCa. Immunohistochemistry was performed on tumor tissue of 81 patients, including 15 patients with HRD-PCa. Peripheral TCR sequencing was performed in a partially overlapping cohort of 48 patients, including 16 patients with HRD-PCa. HRD patients more frequently had intratumoral CD3 + , CD3 + CD8 − FoxP3 − or Foxp3 + TILs above median compared to patients without DNA damage repair alterations (DDRwt; CD3 + and Foxp3 + : 77% vs 35%, p = .013; CD3 + CD8 − FoxP3 − : 80% vs 44%, p = .031). No significant difference in CD8 + TILs or PD-L1 expression was observed. In peripheral blood, HRD patients displayed a more diverse TCR repertoire compared to DDRwt patients (p = .014). Additionally, HRD patients shared TCR clusters with low generation probability, suggesting patient-overlapping T cell responses. A pooled analysis of clinical data from 227 patients with molecularly characterized PCa suggested increased efficacy of ICIs in HRD-PCa. In conclusion, patients with HRD-PCa display increased TIL density and an altered peripheral TCR repertoire. Further research into the efficacy of ICIs and the presence of shared neoantigens in HRD-PCa is warranted.

Homologous Recombination Repair Gene Mutations in Prostate Cancer: Prevalence and Clinical Value

“…The higher levels of immunosuppressive immune cells infiltrating the tumor may explain the low response rates to immune checkpoint inhibition observed in patients with PC harboring CDK12 mutations. The findings of van Wilpe et al [ 77 ] support the view that PC with HRD should be considered an immunologically distinct subtype characterized by an altered peripheral T cell receptor repertoire. Although these findings suggest that CDK12 loss is associated with limited susceptibility to immune checkpoint inhibition in patients with PC, larger prospective clinical trials are required to determine the clinical value of immunotherapy in patients with CDK12 -mutant PC.…”