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

Chang, Liu; Somasundaram, Ashwin; Manne, Sasikanth; Gocher, Angela M.; Szymczak-Workman, Andrea L.; Vignali, Kate M.; Scott, Ellen; Normolle, Daniel P.; Wherry, E. John; Lipson, Evan J.; Ferris, Robert L.; Bruno, Tullia C.; Workman, Creg J.

doi:10.1038/s41590-020-0733-2

Cited by 94 publications

(95 citation statements)

References 55 publications

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“…Nevertheless, with the E8I Cre Nrp1 L/L mice we also observed clear synergy between genetic ablation of Nrp1 and PD1 blockade in the MC38 colon adenocarcinoma model, further supporting the notion that NRP1 contributes to, although indirectly, the defective CD8 + T cell-mediated primary tumor control. 104 In fact, the most striking phenotype of the E8I Cre Nr-p1 L/L mice is their improved protection against secondary tumors in a mouse model of postsurgical tumor immunity. 104 This observation suggested a primary role for NRP1 in CD8 + T cells may be it contributes to the defective CD8 + T cell-mediated immunological memory against tumors.…”

Section: Nrp1 In T Reg Cells: the Guardian Of Intratumoral T Reg Cellmentioning

confidence: 99%

“…104 In fact, the most striking phenotype of the E8I Cre Nr-p1 L/L mice is their improved protection against secondary tumors in a mouse model of postsurgical tumor immunity. 104 This observation suggested a primary role for NRP1 in CD8 + T cells may be it contributes to the defective CD8 + T cell-mediated immunological memory against tumors. Of clinical significance, this model resembles control of disease relapse in patients with cancer.…”

Section: Nrp1 In T Reg Cells: the Guardian Of Intratumoral T Reg Cellmentioning

confidence: 99%

Section: Nrp1 On Cd8 + T Cells: the Link Between Tmentioning

confidence: 99%

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Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

Chuckran

Liu

Bruno

et al. 2020

J Immunother Cancer

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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 (Treg cells). In this context, the immunoregulatory receptor Neuropilin-1 (NRP1) is garnering renewed attention as it reinforces intratumoral Treg cell function amidst inflammation in the TME. Loss of NRP1 on Treg cells in mouse models restores antitumor immunity without sacrificing peripheral tolerance. Enrichment of NRP1+ Treg cells is observed in patients across multiple malignancies with cancer, both intratumorally and in peripheral sites. Thus, targeting NRP1 may safely undermine intratumoral Treg 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.

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Section: Nrp1 In T Reg Cells: the Guardian Of Intratumoral T Reg Cellmentioning

confidence: 99%

Section: Nrp1 In T Reg Cells: the Guardian Of Intratumoral T Reg Cellmentioning

confidence: 99%

Section: Nrp1 On Cd8 + T Cells: the Link Between Tmentioning

confidence: 99%

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Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

Chuckran

Liu

Bruno

et al. 2020

J Immunother Cancer

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“…This in turn restricts the anti-tumor immune response. [ 41 – 44 ] In mouse models, knockout of the NRP1 gene acting on Tregs could reduce tumor growth. This highlights the importance of NRP1 in suppressing anti-tumor immunity.…”

Section: Nrp1 Functions In a Variety Of Immune Cellsmentioning

confidence: 99%

Targeting neuropilin-1 interactions is a promising anti-tumor strategy

Liu

Zhong

et al. 2020

Chinese Medical Journal

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Neuropilins (NRP1 and NRP2) are multifunctional receptor proteins that are involved in nerve, blood vessel, and tumor development. NRP1 was first found to be expressed in neurons, but subsequent studies have demonstrated its surface expression in cells from the endothelium and lymph nodes. NRP1 has been demonstrated to be involved in the occurrence and development of a variety of cancers. NRP1 interacts with various cytokines, such as vascular endothelial growth factor family and its receptor and transforming growth factor β1 and its receptor, to affect tumor angiogenesis, tumor proliferation, and migration. In addition, NRP1 + regulatory T cells (Tregs) play an inhibitory role in tumor immunity. High numbers of NRP1 + Tregs were associated with cancer prognosis. Targeting NRP1 has shown promise, and antagonists against NRP1 have had therapeutic efficacy in preliminary clinical studies. NRP1 treatment modalities using nanomaterials, targeted drugs, oncolytic viruses, and radio-chemotherapy have gradually been developed. Hence, we reviewed the use of NRP1 in the context of tumorigenesis, progression, and treatment.

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“…NRP1 may be a promising target for cancer immunotherapy. CD8 + T cell-restricted NRP1-deficient mice are significantly more sensitive to PD1 immunotherapy [13]. The high proportion of NRP1 -/regulatory T cells (Tregs) in the tumor enhances anti-tumor immunity and promotes tumor clearance [14].…”

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confidence: 99%

Loss of neuropilin1 inhibits liver cancer stem cells population and blocks metastasis in hepatocellular carcinoma via epithelial-mesenchymal transition

Zhou

et al. 2021

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

Cited by 94 publications

References 55 publications

Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

Neuropilin-1: a checkpoint target with unique implications for cancer immunology and immunotherapy

Targeting neuropilin-1 interactions is a promising anti-tumor strategy

Loss of neuropilin1 inhibits liver cancer stem cells population and blocks metastasis in hepatocellular carcinoma via epithelial-mesenchymal transition

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