Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1

Marine Leclerc, Elodie Voilin, Gwendoline Gros, Stéphanie Corgnac, Vincent Montpréville, Pierre Validire, Georges Bismuth and Fathia Mami-Chouaib ()
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Marine Leclerc: INSERM UMR 1186, Gustave Roussy, EPHE, PSL, Faculté de Médecine-Université Paris-Sud, Université Paris-Saclay
Elodie Voilin: INSERM UMR 1186, Gustave Roussy, EPHE, PSL, Faculté de Médecine-Université Paris-Sud, Université Paris-Saclay
Gwendoline Gros: INSERM UMR 1186, Gustave Roussy, EPHE, PSL, Faculté de Médecine-Université Paris-Sud, Université Paris-Saclay
Stéphanie Corgnac: INSERM UMR 1186, Gustave Roussy, EPHE, PSL, Faculté de Médecine-Université Paris-Sud, Université Paris-Saclay
Vincent Montpréville: INSERM UMR 1186, Gustave Roussy, EPHE, PSL, Faculté de Médecine-Université Paris-Sud, Université Paris-Saclay
Pierre Validire: Institut Mutualiste Montsouris, Service d’Anatomie pathologique
Georges Bismuth: INSERM U1016, Institut Cochin
Fathia Mami-Chouaib: INSERM UMR 1186, Gustave Roussy, EPHE, PSL, Faculté de Médecine-Université Paris-Sud, Université Paris-Saclay

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Neuropilin-1 (Nrp-1) is a marker for murine CD4+FoxP3+ regulatory T (Treg) cells, a subset of human CD4+ Treg cells, and a population of CD8+ T cells infiltrating certain solid tumours. However, whether Nrp-1 regulates tumour-specific CD8 T-cell responses is still unclear. Here we show that Nrp-1 defines a subset of CD8+ T cells displaying PD-1hi status and infiltrating human lung cancer. Interaction of Nrp-1 with its ligand semaphorin-3A inhibits migration and tumour-specific lytic function of cytotoxic T lymphocytes. In vivo, Nrp-1+PD-1hi CD8+ tumour-infiltrating lymphocytes (TIL) in B16F10 melanoma are enriched for tumour-reactive T cells exhibiting an exhausted state, expressing Tim-3, LAG-3 and CTLA-4 inhibitory receptors. Anti-Nrp-1 neutralising antibodies enhance the migration and cytotoxicity of Nrp-1+PD-1hi CD8+ TIL ex vivo, while in vivo immunotherapeutic blockade of Nrp-1 synergises with anti-PD-1 to enhance CD8+ T-cell proliferation, cytotoxicity and tumour control. Thus, Nrp-1 could be a target for developing combined immunotherapies.

Date: 2019
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DOI: 10.1038/s41467-019-11280-z

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