Loss and Promoter Hypermethylation Negatively Predict for Immunogenicity in BRCA-Deficient Ovarian Cancer.

Purpose: Ovarian cancers can exhibit a prominent immune infiltrate, but clinical trials have not demonstrated substantive response rates to immune checkpoint blockade monotherapy. We aimed to understand genomic features associated with immunogenicity in mutation-associated cancers.

Materials And Methods: Using the Cancer Genome Atlas whole-exome sequencing, methylation, and expression data, we analyzed 66 ovarian cancers with either germline or somatic loss of and whole-exome sequencing, immunohistochemistry, and CyTOF in 20 ovarian cancers with germline pathogenic variants from Penn.

Results: We found two groups of ovarian cancers differing in their immunogenicity: (1) 37 tumors significantly enriched for loss (11, 30%) and promoter-hypermethylated (10, 27%; = .0016) and (2) wild-type (28 of 29 tumors) cancers, with the latter group having longer overall survival (OS; = .0186, median OS not reached median OS = 66.1 months). -mutant loss and promoter-hypermethylated cancers were characterized by the decreased composition of lymphocytes estimated by gene expression ( = .0030), cytolytic index ( = .034), and cytokine expression but higher homologous recombination deficiency scores ( = .00013). Large-scale state transitions were the primary discriminating feature ( = .001); neither mutational burden nor neoantigen burden could explain differences in immunogenicity. In Penn tumors, loss and high homologous recombination deficiency cancers exhibited fewer CD3+ ( = .05), CD8+ ( = .012), and FOXP3+ ( = .0087) T cells; decreased PRF1 expression ( = .041); and lower immune costimulatory and inhibitory molecule expression.

Conclusion: Our study suggests that within ovarian cancers with genetic loss of are two subsets exhibiting differential immunogenicity, with lower levels associated with loss and BRCA hypermethylation. These genomic features of -associated ovarian cancers may inform considerations around how to optimally deploy immune checkpoint inhibitors in the clinic.