Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma
Olivia Le Saux, Maude Ardin, Justine Berthet, Sarah Barrin, Morgane Bourhis, Justine Cinier, Yasmine Lounici, Isabelle Treilleux, Pierre-Alexandre Just, Guillaume Bataillon, Aude-Marie Savoye, Marie‐Ange Mouret‐Reynier, Elodie Coquan, Olfa Derbel, Louis Jeay, Suliman Bouizaguen, Sana Intidhar Labidi‐Galy, Séverine Tabone‐Eglinger, Anthony Ferrari, Emilie Thomas, Christine Ménétrier‐Caux, Éric Tartour, Isabelle Galy–Fauroux, Marc‐Henri Stern, Magali Terme, Christophe Caux, Bertrand Dubois, Isabelle Ray‐Coquard
Abstract
Abstract PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8 + PD-1 + T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2 + endothelial cells, could overcome immune resistance of ovarian cancers.