Biochemistry, Department of

 

Authors

Filippo Veglia, The Wistar Institute, Philadelphia
Vladimir A. Tyurin, University of Pittsburgh
Maria Blasi, Duke University School of Medicine
Alessandra De Leo, The Wistar Institute, Philadelphia
Andrew Kossenkov, The Wistar Institute, Philadelphia
Laxminarasimha Donthireddy, The Wistar Institute, Philadelphia
To Tsun Ki Jerrick, University of Pennsylvania School of Medicine
Zach Schug, The Wistar Institute, Philadelphia
Subhasree Basu, The Wistar Institute, Philadelphia
Fang Wang, The Wistar Institute, Philadelphia
Emanuela Ricciotti, University of Pennsylvania School of Medicine
Concetta C. DiRusso, University of Nebraska - LincolnFollow
Maureen E. Murphy, The Wistar Institute, Philadelphia
Robert H. Vonderheide, University of Pennsylvania School of Medicine
Paul M. Lieberman, The Wistar Institute, Philadelphia
Charles Mulligan, Helen F Graham Cancer Center at Christiana Care Health System, Wilmington, DE
Brian Nam, Helen F Graham Cancer Center at Christiana Care Health System, Wilmington, DE
Neil Hockstein, Helen F Graham Cancer Center at Christiana Care Health System, Wilmington, DE
Gregory Masters, University of Pennsylvania School of Medicine
Michael Guarino, Helen F Graham Cancer Center at Christiana Care Health System, Wilmington, DE
Cindy Lin, The Wistar Institute, Philadelphia
Yulia Nefedova, The Wistar Institute, Philadelphia
Paul N. Black, University of Nebraska-LincolnFollow
Valerian E, Kagan, University of Pittsburgh
Dmitry Gabrilovich, The Wistar Institute, PhiladelphiaFollow

Document Type

Article

Date of this Version

2019

Citation

Published in final edited form as: Nature. 2019 May ; 569(7754): 73–78. doi:10.1038/s41586-019-1118-2.

Comments

HHS Public Access Author manuscript Nature. Author manuscript; available in PMC 2019 October 17.

Abstract

Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that are critically important for the regulation of immune responses in cancer. They contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limits selective targeting of these cells. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSC. The main mechanism of FATP2 mediated suppressive activity involved uptake of arachidonic acid (AA) and synthesis of prostaglandin E2 (PGE2). The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to selectively inhibit the functions of PMN-MDSC and improve the effect of cancer therapy.

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