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, Intidhar Labidi-Galy, Séverine Tabone-Eglinger, Anthony Ferrari, Emilie Thomas, Christine Ménétrier-Caux, Eric Tartour, Isabelle Galy-Fauroux, Marc-Henri Stern, Magali Terme, Christophe Caux, Bertrand Dubois () and Isabelle Ray-Coquard ()
Additional contact information
Olivia Le Saux: Université de Lyon, Université Claude Bernard Lyon 1
Maude Ardin: Université de Lyon, Université Claude Bernard Lyon 1
Justine Berthet: Université de Lyon, Université Claude Bernard Lyon 1
Sarah Barrin: Centre Léon Bérard
Morgane Bourhis: PARCC
Justine Cinier: Université de Lyon, Université Claude Bernard Lyon 1
Yasmine Lounici: Université de Lyon, Université Claude Bernard Lyon 1
Isabelle Treilleux: Centre Léon Bérard
Pierre-Alexandre Just: AP-HM
Guillaume Bataillon: University hospital of Toulouse
Aude-Marie Savoye: National Investigators Group for Ovarian and Breast Cancer Studies
Marie-Ange Mouret-Reynier: National Investigators Group for Ovarian and Breast Cancer Studies
Elodie Coquan: National Investigators Group for Ovarian and Breast Cancer Studies
Olfa Derbel: Hôpital Privé Jean Mermoz
Louis Jeay: now Tribun Health
Suliman Bouizaguen: now Tribun Health
Intidhar Labidi-Galy: Center of Translational Research in Onco-Hematology, Swiss Cancer Center Leman
Séverine Tabone-Eglinger: Centre Léon Bérard
Anthony Ferrari: Centre Léon Bérard
Emilie Thomas: Centre Léon Bérard
Christine Ménétrier-Caux: Université de Lyon, Université Claude Bernard Lyon 1
Eric Tartour: PARCC
Isabelle Galy-Fauroux: PARCC
Marc-Henri Stern: Institut Curie, PSL Research University
Magali Terme: PARCC
Christophe Caux: Université de Lyon, Université Claude Bernard Lyon 1
Bertrand Dubois: Université de Lyon, Université Claude Bernard Lyon 1
Isabelle Ray-Coquard: Centre Léon Bérard

Nature Communications, 2024, vol. 15, issue 1, 1-15

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.

Date: 2024
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DOI: 10.1038/s41467-024-47000-5

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