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

Anniina Färkkilä, Doga C. 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 Munster, Sandro Santagata, Elizabeth Garcia, Scott 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 () and Panagiotis A. Konstantinopoulos ()
Additional contact information
Anniina Färkkilä: Dana-Farber Cancer Institute
Doga C. Gulhan: Harvard Medical School
Julia Casado: University of Helsinki
Connor A. Jacobson: Harvard Medical School
Huy Nguyen: Dana-Farber Cancer Institute
Bose Kochupurakkal: Dana-Farber Cancer Institute
Zoltan Maliga: Harvard Medical School
Clarence Yapp: Harvard Medical School
Yu-An Chen: Harvard Medical School
Denis Schapiro: Harvard Medical School
Yinghui Zhou: TESARO: A GSK company
Julie R. Graham: TESARO: A GSK company
Bruce J. Dezube: TESARO: A GSK company
Pamela Munster: Helen Diller Family Comprehensive Cancer Center
Sandro Santagata: Laboratory for Systems Pharmacology
Elizabeth Garcia: Harvard Medical School
Scott Rodig: Harvard Medical School
Ana Lako: Harvard Medical School
Dipanjan Chowdhury: Dana-Farber Cancer Institute
Geoffrey I. Shapiro: Dana-Farber Cancer Institute
Ursula A. Matulonis: Dana-Farber Cancer Institute
Peter J. Park: Harvard Medical School
Sampsa Hautaniemi: University of Helsinki
Peter K. Sorger: Harvard Medical School
Elizabeth M. Swisher: University of Washington
Alan D. D’Andrea: Dana-Farber Cancer Institute
Panagiotis A. Konstantinopoulos: Dana-Farber Cancer Institute

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15315-8

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