Fatty acid transport protein 2 reprograms neutrophils in cancer

Filippo Veglia, Vladimir A. Tyurin, Maria Blasi, Alessandra De 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 GuarinoCindy Lin, Yulia Nefedova, Paul Black, Valerian E. Kagan, Dmitry I. Gabrilovich

Research output: Contribution to journalArticle

59 Scopus citations

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 E 2 . 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.

Original languageEnglish (US)
Pages (from-to)73-78
Number of pages6
JournalNature
Volume569
Issue number7754
DOIs
StatePublished - May 2 2019

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    Veglia, F., Tyurin, V. A., Blasi, M., De Leo, A., Kossenkov, A. V., Donthireddy, L., To, T. K. J., Schug, Z., Basu, S., Wang, F., Ricciotti, E., DiRusso, C., Murphy, M. E., Vonderheide, R. H., Lieberman, P. M., Mulligan, C., Nam, B., Hockstein, N., Masters, G., ... Gabrilovich, D. I. (2019). Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature, 569(7754), 73-78. https://doi.org/10.1038/s41586-019-1118-2