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

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.