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.