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

Marine Leclerc,Pierre Validire,Elodie Voilin,Vincent De Montpréville,Stéphanie Corgnac,Gwendoline Gros,Georges Bismuth,Fathia Mami-Chouaib

doi:10.1038/s41467-019-11280-z

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.

Highlights

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
Cytotoxic T lymphocytes (CTL) must first migrate to the tumour site, infiltrate tumour cell clusters, and interact with malignant cells to achieve their cytotoxic functions after T-cell receptor (TCR) recognition of specific tumour peptide-major histocompatibility complex class I (MHC-I) complexes on target cells[1]
It should be noted that most Nrp-1 was found on FoxP3− CD4+ T cells expressing PD-1, Tim-3 and CTLA-4, as well as Ki-67 (Supplementary Fig. 5f, g). These results indicate that Nrp-1 characterises an intra-tumoural CD8+ T-cell subset displaying a highly activated PD-1hi status with co-expression of several T-cell inhibitory receptors, like CTLA-4, Tim-3 and LAG-3, involved in immune suppression during cancer diseases, and among which Nrp-1 may play an important role by repulsing activated T cells from the site of ongoing antitumour immune responses

Summary

Introduction

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. CTL must first migrate to the tumour site, infiltrate tumour cell clusters, and interact with malignant cells to achieve their cytotoxic functions after T-cell receptor (TCR) recognition of specific tumour peptide-major histocompatibility complex class I (MHC-I) complexes on target cells[1]. PD-1 expression on CD8+ TIL seems to be a characteristic of clonally expanded CD8+ tumour-reactive T cells identified in cancer patients[3] In this context, elucidating the mechanisms of CTLA-4 and PD-1 T-cell inhibitory signalling has led to development of promising cancer immunotherapy tools, including blocking monoclonal antibodies (mAb) targeting these so-called ‘immune checkpoints'[4,5]. We conclude that Nrp-1 is an immune checkpoint that negatively regulates antitumour CD8+ T-cell immunity, and is a promising target for combination cancer immunotherapies

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