The BRCA2 mutation status shapes the immune phenotype of prostate cancer

Maximilian Jenzer,Dirk Jäger,Carsten Grüllich,Holger Sültmann,Fabian Stögbauer,Peter Keß,Stefanie Zschäbitz,Anette Duensing,Markus Hohenfellner,Anna‐Lena Volckmar ,Brian A Kudlow ,Jonas Leichsenring,Albrecht Stenzinger,Skyler Mishkin,Volker Endris,Maximilian Kippenberger,Peter Schirmacher,Adam Kaczorowski,Josh Haimes,Cathleen Nientiedt,Stefan Duensing

doi:10.1007/s00262-019-02393-x

Abstract

Defects in DNA damage repair caused by mutations in BRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation between BRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eight BRCA2-mutated tumors in comparison with eight BRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyzed seven prostate cancer biopsies that were either BRCA2 or ATM-mutated in comparison with wild-type tumors. Whereas in BRCA1/2 wild-type tumors, immune cells were found predominantly extratumorally, most BRCA2-mutated tumors including one biopsy showed a significantly increased intratumoral immune cell infiltration. The ratio of intratumoral to extratumoral immune cells was considerably higher in BRCA2-mutated tumors for all markers and reached statistical significance for CD4 (p = 0.007), CD8 (p = 0.006), and FOXP3 (p = 0.001). However, the intratumoral CD8 to FOXP3 ratio showed a trend to be lower in BRCA2-mutated tumors suggesting a more suppressed tumor immune microenvironment. Our findings provide a rationale for the future use of immune oncological approaches in BRCA2-mutated prostate cancer and may encourage efforts to target immunosuppressive T-cell populations to prime tumors for immunotherapy.

Highlights

Prostate cancer is the most common non-cutaneous cancer in men and the second leading cause of death from cancer in men in the USA and worldwide [1, 2]
Eight BRCA2-mutated prostate cancer patients and eight BRCA1/2 wild-type patients matched for age, Gleason score, initial PSA, and initial TNM state were selected for this retrospective analysis
The overall frequency of these cells was low and slightly higher in BRCA2-mutated tumors in comparison with wild-type tumors albeit without reaching statistical significance (p = 0.2). These results demonstrate that BRCA2mutated tumors contain an increased number of intratumoral immune cells when compared to BRCA1/2 wild-type tumors in particular CD4- and FOXP3-positive cells

Summary

Introduction

Prostate cancer is the most common non-cutaneous cancer in men and the second leading cause of death from cancer in men in the USA and worldwide [1, 2]. HR deficiency caused by hereditary and/or somatic mutations in BRCA1/2 or other DNA repair genes have been found in breast cancer and in other types of cancer including ovarian or prostate cancer [3]. BRCA1/2-deficient prostate cancers show increased sensitivity to platinum-based chemotherapies [11], and to poly-(ADP-ribose) polymerase (PARP) inhibitors [12,13,14], giving BRCA1/2 deficiency a high clinical relevance in these patients [15, 16]

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Results

Conclusion