Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1

Julien Rossignol; Zakia Belaid; Guillemette Fouquet; Flavia Guillem; Rachel Rignault; Pierre Milpied; Amédée Renand; Tereza Coman; Maud D'Aveni; Michael Dussiot; Elia Colin; Jonathan Levy; Caroline Carvalho; Nicolas Goudin; Nicolas Cagnard; Francine Côté; Joel Babdor; Kanit Bhukhai; Laura Polivka; Amélie E Bigorgne; Héloise Halse; Aurélien Marabelle; Séverine Mouraud; Yves Lepelletier; Thiago T Maciel; Marie-Thérèse Rubio; Delphine Heron; Caroline Robert; Isabelle Girault; Doris Lebeherec; Jean-Yves Scoazec; Ivan Moura; Louise Condon; Mirjana Weimershaus; Franck Pages; Jean Davoust; David Gross; Olivier Hermine

doi:10.1016/j.isci.2022.104353

Neuropilin-1 cooperates with PD-1 in CD8⁺ T cells predicting outcomes in melanoma patients treated with anti-PD1

iScience. 2022 May 5;25(6):104353. doi: 10.1016/j.isci.2022.104353. eCollection 2022 Jun 17.

Authors

Julien Rossignol^{1

2

3}, Zakia Belaid^{1

2}, Guillemette Fouquet^{1

2}, Flavia Guillem^{1

2}, Rachel Rignault^{1

2}, Pierre Milpied^{1

2

4}, Amédée Renand^{1

2}, Tereza Coman^{1

2}, Maud D'Aveni^{1

2}, Michael Dussiot^{1

2}, Elia Colin^{1

2}, Jonathan Levy⁵, Caroline Carvalho^{1

2}, Nicolas Goudin⁶, Nicolas Cagnard⁷, Francine Côté^{1

2}, Joel Babdor^{1

2}, Kanit Bhukhai^{1

2}, Laura Polivka^{1

2}, Amélie E Bigorgne^{1

2

8}, Héloise Halse¹, Aurélien Marabelle⁸, Séverine Mouraud⁸, Yves Lepelletier^{1

2}, Thiago T Maciel^{1

2}, Marie-Thérèse Rubio^{1

2}, Delphine Heron⁹, Caroline Robert¹⁰, Isabelle Girault¹⁰, Doris Lebeherec¹¹, Jean-Yves Scoazec¹¹, Ivan Moura^{1

2}, Louise Condon^{1

2}, Mirjana Weimershaus^{1

2}, Franck Pages¹², Jean Davoust¹³, David Gross¹³, Olivier Hermine^{1

2

3}

Affiliations

¹ Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR) 1163, 75015 Paris, France.
² Sorbonne Paris Cité, Université René Descartes, Imagine Institute, 75015 Paris, France.
³ Department of Hematology, Hôpital Necker, 75015 Paris, France.
⁴ Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France.
⁵ Department of Genetics, Hopital Robert Debré, 75019 Paris, France.
⁶ Structure Fédérative de Recherche (SFR) Necker, Inserm US 24 CNRS UMS 3633, Cell Imaging Platform UMS 24, Hôpital Necker Enfants Malades, Bâtiment Imagine, 24 boulevard du Montparnasse, 75015 Paris, France.
⁷ Paris-Descartes Bioinformatics Platform, 75015 Paris, France.
⁸ Departement Innovation Thérapeutique et Essais Precoces (DITEP), Gustave Roussy Cancer Campus (GRCC), 114 rue Edouard Vaillant, 94805 Villejuif, France.
⁹ Department of Genetics, Assistance Publique - Hôpitaux de Paris, University Hôpital Pitié-Salpêtrière, 75013 Paris, France.
¹⁰ Department of Dermatology, Department of Medicine and Paris-Sud University, Gustave Roussy, 94805 Villejuif, France.
¹¹ Department of Pathology, Gustave-Roussy Cancer Campus, 94805, Villejuif, France.
¹² INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, 75006 Paris, France.
¹³ Institut Necker Enfants Malades (INEM), INSERM U1151, CNRS UMR8253, Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France.

Abstract

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8⁺ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1⁺CD8⁺ T cells, cooperates and enhances PD-1 activity. In mice, CD8⁺ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8⁺ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.

Keywords: Cancer; Immunology.