Neuropilin-1 is a T cell memory checkpoint limiting long-term antitumor immunity

Nat Immunol. 2020 Sep;21(9):1010-1021. doi: 10.1038/s41590-020-0733-2. Epub 2020 Jul 13.


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 Tmem that are essential for durable antitumor immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Humans
  • Immune Checkpoint Proteins / genetics
  • Immune Checkpoint Proteins / metabolism*
  • Immune Tolerance
  • Immunity
  • Immunologic Memory
  • Melanoma, Experimental / immunology*
  • Mice
  • Mice, Knockout
  • Neuropilin-1 / genetics
  • Neuropilin-1 / metabolism*
  • Precursor Cells, T-Lymphoid / immunology*
  • Programmed Cell Death 1 Receptor / metabolism
  • Signal Transduction


  • Immune Checkpoint Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Neuropilin-1