Homologous recombination repair deficient prostate cancer represents an immunologically distinct subtype

Sandra van Wilpe, Donjetë Simnica, Peter Slootbeek, Thomas van Ee, Samhita Pamidimarri Naga, Mark A.J. Gorris, Lieke L. van der Woude, Shabaz Sultan, Rutger H.T. Koornstra, Inge M. van Oort, Winald R. Gerritsen, Leonie I. Kroeze, Michiel Simons, Geert J.L.H. van Leenders, Mascha Binder, I. Jolanda M. de Vries, Niven Mehra*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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+CD8FoxP3 or Foxp3+ TILs above median compared to patients without DNA damage repair alterations (DDRwt; CD3+ and Foxp3+: 77% vs 35%, p = .013; CD3+CD8FoxP3: 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.

Original languageEnglish
Article number2094133
JournalOncoImmunology
Volume11
Issue number1
DOIs
Publication statusE-pub ahead of print - 1 Jul 2022

Bibliographical note

Funding Information:
We thank all participants that provided biomaterial for this study. Shabaz Sultan was supported by the Dutch Cancer Society – Alpe d’HuZes foundation (grant 10620).

Funding Information:
This research was partly funded by Roche Diagnostics the Netherlands. The funding organization had no role in the design and conduct of the study, collection, management, analysis, interpretation of the data, and preparation, review, or approval of the abstract or the manuscript. We thank all participants that provided biomaterial for this study. Shabaz Sultan was supported by the Dutch Cancer Society–Alpe d’HuZes foundation (grant 10620).

Publisher Copyright:
© 2022 Radboud University Medical Center. Published with license by Taylor & Francis Group, LLC.

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