Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer.

ABSTRACT: Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8?+?T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8?+?T-cells and PD-L1?+?macrophages and PD-L1?+?tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8?+?T-cells with PD-L1?+?macrophages in the first, and exhausted CD8?+?T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.

SUBMITTER: Farkkila A 

PROVIDER: S-EPMC7081234 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature