Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy
Open Access
- 1 January 2020
- journal article
- review article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (2), e000967
- https://doi.org/10.1136/jitc-2020-000967
Abstract
Checkpoint blockade immunotherapy established a new paradigm in cancer treatment: for certain patients curative treatment requires immune reinvigoration. Despite this monumental advance, only 20%-30% of patients achieve an objective response to standard of care immunotherapy, necessitating the consideration of alternative targets. Optimal strategies will not only stimulate CD8(+) T cells, but concomitantly modulate immunosuppressive cells in the tumor microenvironment (TME), most notably regulatory T cells (T-reg cells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral T-reg cell function amidst inflammation in the TME. Loss of NRP1 on T(reg)cells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1(+) T-reg cells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral T-reg cell fitness, permitting enhanced inflammatory responses with existing immunotherapies. Furthermore, NRP1 has been recently found to modulate tumor-specific CD8(+) T cell responses. Emerging data suggest that NRP1 restricts CD8(+) T cell reinvigoration in response to checkpoint inhibitors, and more importantly, acts as a barrier to the long-term durability of CD8(+) T cell-mediated tumor immunosurveillance. These novel and distinct regulatory mechanisms present an exciting therapeutic opportunity. This review will discuss the growing literature on NRP1-mediated immune modulation which provides a strong rationale for categorizing NRP1 as both a key checkpoint in the TME as well as an immunotherapeutic target with promise either alone or in combination with current standard of care therapeutic regimens.Funding Information
- NCI Predoctoral Fellowship Award (F31 CA243168)
- National Institutes of Health (P01 AI108545, R01 CA203689)
This publication has 117 references indexed in Scilit:
- Signatures of mutational processes in human cancerNature, 2013
- Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced CancerThe New England Journal of Medicine, 2012
- Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in CancerThe New England Journal of Medicine, 2012
- Improved Survival with Ipilimumab in Patients with Metastatic MelanomaThe New England Journal of Medicine, 2010
- Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) InteractionJournal of Medicinal Chemistry, 2010
- Neuropilin-1 antagonism in human carcinoma cells inhibits migration and enhances chemosensitivityBritish Journal of Cancer, 2010
- Neuropilin-1 Expression on Regulatory T Cells Enhances Their Interactions with Dendritic Cells during Antigen RecognitionImmunity, 2008
- Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patientsProceedings of the National Academy of Sciences of the United States of America, 2008
- Foxp3 occupancy and regulation of key target genes during T-cell stimulationNature, 2007
- VEGF165 mediates formation of complexes containing VEGFR‐2 and neuropilin‐1 that enhance VEGF165‐receptor bindingJournal of Cellular Biochemistry, 2002