The tumor immune microenvironment of germline BRCA1/2 and sporadic prostate cancer.

Abstract

152 Background: Prostate cancer (PC) is considered an immunologically ‘cold’ tumor and therefore patients are generally not considered good candidates for immunotherapy. Tumors arising in germline (g) BRCA1/2 mutation carriers are associated with higher genomic instability and levels of immune infiltration in breast and ovarian cancer. We investigated how germline mutations in DNA repair genes affect the tumor immune microenvironment (TME) of PC. Methods: Archival primary tumor samples from 26 patients with g BRCA2 mutations, 5 with g BRCA1, 5 with mutations in other DNA repair genes ( ATM, CHEK2, FANCI, PALB2 or BRCA2+ MSH2), and 26 sporadic patients were analyzed. OPAL multiplex immunohistochemistry was used to detect 7 markers (CD3, CD4, CD8, FOXP3, PDL1, AMACR, DAPI) to identify immune subsets and provide the X,Y coordinates of single cells. We developed novel computational distance-based methods to characterize the spatial distribution of cells. Gene expression was evaluated with the Nanostring panel of 770 immune genes. Results: g BRCA1/2 carriers showed lower levels of T cells (9.73% of the tumor stroma) compared to sporadic tumors (14.8%). In in both cothors the T cell population was dominated by CD4+ cells (69.5%), with CD8+ cells representing only 25.6%. Sporadic PCs displayed aggregation of T cells into large clusters in the stroma dominated by CD4+ cells and few CD8+ cells, while 77% of high-grade g BRCA2 patients were enriched in high levels of free, non-aggregated CD8+ T-cells in the tumor area. HLA-A expression was 2.37 times higher in g BRCA2 patients ( p = 3.4x10−8), who also showed higher expression of genes associated with a present but suppressed immune system ( p = 1.4x10−4). gBRCA2 patients with larger T-cell aggregates had an overall poorer prognosis compared to patients without (time to metastasis 55.1 vs. 85.3 months, survival time 67.3 vs. 85.0 months). Conclusions: g BRCA2 carriers displayed higher levels of HLA-A, more free CD8+ T cells infiltrating tumor regions and higher inflammatory signatures, suggesting an immune system that could potentially be harnessed. The degree of clustering of T cells (free vs. aggregated) within the TME may provide valuable prognostic information that warrants further validation.