Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer
Anniina Färkkilä, D. Gulhan, Julia Casado, Connor A. Jacobson, Huy Nguyen, Bose Kochupurakkal, Zoltan Maliga, Clarence Yapp, Yu‐An Chen, Denis Schapiro, Yinghui Zhou, Julie R. Graham, Bruce J. Dezube, Pamela N. Münster, Sandro Santagata, Elizabeth Garcia, Scott J. Rodig, Ana Lako, Dipanjan Chowdhury, Geoffrey I. Shapiro, Ursula A. Matulonis, Peter J. Park, Sampsa Hautaniemi, Peter K. Sorger, Elizabeth M. Swisher, Alan D. D’Andrea, Panagiotis A. Konstantinopoulos
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.