Study Results May Help Improve Cancer Immunotherapy

The protein Neuropilin-1 (Nrp1) is required to maintain Treg stability and function. NRP1 is a membrane-bound co-receptor to a tyrosine kinase receptor for both vascular endothelial growth factor (VEGF) and semaphorin family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion and has been implicated in the vascularization and progression of cancers. NRP1 expression has been shown to be elevated in a number of human patient tumor samples, including brain, prostate, breast, colon, and lung cancers and NRP1 levels are positively correlated with metastasis.

Investigators at the University of Pittsburgh School of Medicine (PA, USA) sought to identify the basis for Tregs' Nrp1 dependency and the key drivers of Treg fragility. This information could help to improve immunotherapy for human cancers.

The investigators worked with a genetically engineered mouse model in which the Nrp1 gene was deleted in half the Treg cell population. They reported in the June 1, 2017, issue of the journal Cell that that a high proportion of Tregs lacking Nrp1 produced interferon-gamma (IFNgamma), which drove the fragility of surrounding wild-type Tregs, boosted anti-tumor immunity, and facilitated tumor clearance. In contrast, a high percentage of Tregs with functioning NRP1 correlated with poor prognosis in melanoma and head and neck squamous cell carcinoma.

"What we have shown in the current study is that in mice, Nrp1 expression by Tregs is required to maintain their ability to prevent the immune system from clearing the tumor. Interestingly, when Tregs lose Nrp1, they not only fail to suppress, they also become active participants in the anti-tumor immune response," said senior author Dr. Dario Vignali, professor of immunology at the University of Pittsburgh School of Medicine. "Intriguingly, we also found that in cancer patients who had a poor prognosis, the Nrp1-expressing Treg subset was much higher, suggesting that the findings could apply to humans as well."

"While we thought that IFNgamma might impact the function of Tregs and thus influence immunotherapy outcome, the magnitude of the effect really took us by surprise," said Dr. Vignali. "When we deleted the receptor for IFNgamma in Tregs so they were no longer sensitive to the impact of IFNgamma, the immunotherapy drug had absolutely no effect. In essence, IFNgamma seems to make Tregs fragile so that they lose their suppressive function, but only in the tumor. Thus, maybe making Tregs fragile is a critical requirement for effective immunotherapy."

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