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Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1
Julien Rossignol1,2,3, Zakia Belaid1,2, Guillemette Fouquet1,2
1Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR) 1163, 75015 Paris, France.
Abstract:
Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.
Insights
Neuropilin-1 (NRP1) enhances Programmed cell Death 1 (PD1) activity in CD8+ T cells, hindering antitumor responses. Targeting NRP1 may overcome resistance to PD1 therapies in cancer treatment.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Medicine
Background:
- Immune checkpoint inhibitors like Programmed cell Death 1 (PD1) therapies have improved cancer patient survival by restoring antitumor immune responses.
- However, a significant number of patients experience relapse or resistance to these therapies.
- Neuropilin-1 (NRP1), a glycoprotein involved in development and angiogenesis, is also expressed in immune cells.
Purpose of the Study:
- To investigate the role of Neuropilin-1 (NRP1) as a potential immune checkpoint co-receptor.
- To determine if NRP1 modulates CD8+ T cell activity in the context of antitumor immune responses.
- To explore NRP1 as a therapeutic target for overcoming resistance to PD1-based cancer immunotherapies.
Main Methods:
- Investigated the recruitment of NRP1 in the cytolytic synapse of PD1+CD8+ T cells.
- Utilized mouse models with CD8+ T cell-specific deletion of Nrp1 to assess anti-PD1 antibody efficacy.
- Analyzed NRP1 expression in tumor-infiltrating CD8+ T cells from human metastatic melanoma patients treated with anti-PD1 therapy.
Main Results:
- Neuropilin-1 (NRP1) is recruited to the cytolytic synapse of PD1+CD8+ T cells and enhances PD-1 activity.
- CD8+ T cell-specific deletion of Nrp1 in mice improved antitumor immune responses to anti-PD1 antibodies.
- High NRP1 expression in tumor-infiltrating CD8+ T cells from human melanoma patients correlated with poor outcomes following anti-PD1 treatment.
Conclusions:
- Neuropilin-1 (NRP1) acts as a co-receptor that enhances PD-1-mediated immune suppression in CD8+ T cells.
- NRP1 is a potential therapeutic target to overcome resistance to anti-PD1 therapies.
- Targeting NRP1 could improve the efficacy of cancer immunotherapies.
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