Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway

Kevin Alicea-Torres, Emilio Sanseviero, Jun Gui, Jinyun Chen, Filippo Veglia, Qiujin Yu, Laxminarasimha Donthireddy, Andrew Kossenkov, Cindy Lin, Shuyu Fu, Charles Mulligan, Brian Nam, Gregory Masters, Fred Denstman, Joseph Bennett, Neil Hockstein, Agnieszka Rynda-Apple, Yulia Nefedova, Serge Y. Fuchs and Dmitry I. Gabrilovich ()
Additional contact information
Kevin Alicea-Torres: The Wistar Institute
Emilio Sanseviero: The Wistar Institute
Jun Gui: School of Veterinary Medicine University of Pennsylvania
Jinyun Chen: School of Veterinary Medicine University of Pennsylvania
Filippo Veglia: The Wistar Institute
Qiujin Yu: School of Veterinary Medicine University of Pennsylvania
Laxminarasimha Donthireddy: The Wistar Institute
Andrew Kossenkov: The Wistar Institute
Cindy Lin: The Wistar Institute
Shuyu Fu: The Wistar Institute
Charles Mulligan: Helen F. Graham Cancer Center and Research Institute
Brian Nam: Helen F. Graham Cancer Center and Research Institute
Gregory Masters: Helen F. Graham Cancer Center and Research Institute
Fred Denstman: Helen F. Graham Cancer Center and Research Institute
Joseph Bennett: Helen F. Graham Cancer Center and Research Institute
Neil Hockstein: Helen F. Graham Cancer Center and Research Institute
Agnieszka Rynda-Apple: Department of Microbiology and Immunology, Montana State University
Yulia Nefedova: The Wistar Institute
Serge Y. Fuchs: School of Veterinary Medicine University of Pennsylvania
Dmitry I. Gabrilovich: AstraZeneca

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically.

Date: 2021
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DOI: 10.1038/s41467-021-22033-2

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