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

Dipanjan Chowdhury,Panagiotis A Konstantinopoulos,Ana Lako,Peter K Sorger,Yinghui Zhou,James G Graham ,Huy Nguyen,Connor A Jacobson,D Gulhan ,Peter J Park,Bruce J Dezube,Denis Schapiro,Zoltan Maliga,Elizabeth M Swisher,Elizabeth Garcia,Scott J Rodig ,Julia Casado,Geoffrey I Shapiro,Sampsa Hautaniemi,Chen Yuan ,Sandro Santagata,Pamela N Münster ,Bose Kochupurakkal,Ursula A Matulonis,Clarence Yapp,Alan D D’Andrea,Anniina Färkkilä

doi:10.1038/s41467-020-15315-8

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.

Highlights

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking
In a syngeneic genetically engineered mouse model of high-grade serous ovarian cancer driven via concurrent loss of p53 and Brca[1] and overexpression of c-Myc, PARP inhibitor olaparib induced activation of Stimulator of Interferon Genes (STING) pathway accompanied by increased expression of Interferon-beta, PD-L1 and CXCL104
Using advanced genomic analyses and single-cell imaging, we show that mutational signature 3 and interferon signaling in the CD8 + T-cell compartment of the tumor microenvironment determine responses to niraparib plus pembrolizumab in patients enrolled in the TOPACIO trial

Summary

Introduction

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We conducted a phase I/II clinical trial of the PARPi niraparib in combination with the anti-PD-1 antibody pembrolizumab in recurrent ovarian cancer (TOPACIO trial7); the trial enrolled 62 patients with a median of 3 prior lines of therapy (range 1–5). Responses were durable and median duration of response was not reached (range 4.2–14.5+) months Despite this promising activity, many patients did not respond, highlighting the need for predictive biomarkers to identify ovarian cancer patients prospectively who would benefit from the niraparib/pembrolizumab combination. In the context of the TOPACIO trial, known biomarkers of response to PARPi and immune checkpoint blockade were not associated with response to the niraparib/ pembrolizumab combination; these biomarkers include tumor BRCA mutation status, homologous recombination deficiency (HRD) status (assessed by the Myriad HRD test), and PD-L1 status. Using advanced genomic analyses and single-cell imaging, we show that mutational signature 3 and interferon signaling in the CD8 + T-cell compartment of the tumor microenvironment determine responses to niraparib plus pembrolizumab in patients enrolled in the TOPACIO trial

Methods

Results

Conclusion