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Fatty acid transport protein 2 reprograms neutrophils in cancer

Author

Listed:
  • 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
    Helen F. Graham Cancer Center at Christiana Care Health System)

  • 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
    University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Dmitry I. Gabrilovich

    (The Wistar Institute)

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.

Suggested Citation

  • 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 Ricciott, 2019. "Fatty acid transport protein 2 reprograms neutrophils in cancer," Nature, Nature, vol. 569(7754), pages 73-78, May.
    • Handle: RePEc:nat:nature:v:569:y:2019:i:7754:d:10.1038_s41586-019-1118-2
    DOI: 10.1038/s41586-019-1118-2
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    Cited by:

    1. Charlotte R. Bell & Victoria S. Pelly & Agrin Moeini & Shih-Chieh Chiang & Eimear Flanagan & Christian P. Bromley & Christopher Clark & Charles H. Earnshaw & Maria A. Koufaki & Eduardo Bonavita & Sant, 2022. "Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Wenwen Tang & Yi Luan & Qianying Yuan & Ao Li & Song Chen & Stanley Menacherry & Lawrence Young & Dianqing Wu, 2024. "LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Jayna J. Mistry & Charlotte Hellmich & Jamie A. Moore & Aisha Jibril & Iain Macaulay & Mar Moreno-Gonzalez & Federica Palma & Naiara Beraza & Kristian M. Bowles & Stuart A. Rushworth, 2021. "Free fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. Ling Tao & Mahmoud A. Mohammad & Giorgio Milazzo & Myrthala Moreno-Smith & Tajhal D. Patel & Barry Zorman & Andrew Badachhape & Blanca E. Hernandez & Amber B. Wolf & Zihua Zeng & Jennifer H. Foster & , 2022. "MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    5. Yanying Wang & Jing Wang & Xiaoyu Li & Xushen Xiong & Jianyi Wang & Ziheng Zhou & Xiaoxiao Zhu & Yang Gu & Dan Dominissini & Lei He & Yong Tian & Chengqi Yi & Zusen Fan, 2021. "N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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