Fatty acid transport protein 2 reprograms neutrophils in cancer

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

Nature, 2019, vol. 569, issue 7754, 73-78

Abstract: Abstract Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte–macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy.

Date: 2019
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DOI: 10.1038/s41586-019-1118-2

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