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Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity
Open accessAbstract
Robust CD8+ T cell memory is essential for long-term protective immunity but is often compromised in cancer, where T cell exhaustion leads to loss of memory precursors. Immunotherapy via checkpoint blockade may not effectively reverse this defect, potentially underlying disease relapse. Here we report that mice with a CD8+ T cell-restricted neuropilin-1 (NRP1) deletion exhibited substantially enhanced protection from tumor rechallenge and sensitivity to anti-PD1 immunotherapy, despite unchanged primary tumor growth. Mechanistically, NRP1 cell-intrinsically limited the self-renewal of the CD44+PD1+TCF1+TIM3- progenitor exhausted T cells, which was associated with their reduced ability to induce c-Jun/AP-1 expression on T cell receptor restimulation, a mechanism that may contribute to terminal T cell exhaustion at the cost of memory differentiation in wild-type tumor-bearing hosts. These data indicate that blockade of NRP1, a unique 'immune memory checkpoint', may promote the development of long-lived tumor-specific T mem that are essential for durable antitumor immunity.
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“Interestingly, the C-terminal motif of the cleaved S1 subunit can bind to neuropillin-1 (NRP-1),67,68 which negatively influences T cell memory.69”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [69]
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Self-citation
Metadata
- Authors
- Liu, C., Somasundaram, A., Manne, S., Gocher, A. M., Szymczak-Workman, A. L., Vignali, K. M., Scott, E. N., Normolle, D. P., John Wherry, E., Lipson, E. J., Ferris, R. L., Bruno, T. C., Workman, C. J., & Vignali, D. A. A.
- Affiliations
- University of Pittsburgh (US)
- University of Pennsylvania (US)
- UPMC Hillman Cancer Center (US)
- Johns Hopkins University (US)
- Corresponding author
- Vignali, Dario A. A.
- ORCID
- Venue
- Nature Immunology
- Published
- 2020-07-13
- Volume
- 21
- Issue
- 9
- Pages
- 1010-1021
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC7442600
- OpenAlex
- W3040823189
- Cited by
- 151
- References
- 56
- Citations by year
- 2026: 13 · 2025: 36 · 2024: 18 · 2023: 27 · 2022: 31 · 2021: 20 · 2020: 6
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (CA203689, AI108545, CA082084, CA247004-01, AI117950, AI082630, AI112521, AI115712, CA210944)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (CA047904, CA006973, CA097190)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- neuropilin-1, T cell exhaustion, CD8+ T cell memory, immune checkpoint, antitumor immunity, anti-PD-1 therapy, tumor rechallenge, T cell self-renewal
- MeSH terms
- Immune Checkpoint Proteins, Animals, Humans, Immune Tolerance, Immunity, Immunologic Memory, Melanoma, Experimental, Signal Transduction, Mice, Knockout, CD8-Positive T-Lymphocytes, Neuropilin-1, Cell Line, Tumor, Mice, Precursor Cells, T-Lymphoid, Programmed Cell Death 1 Receptor
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