Veglia et al. showed that in PMN-MDSCs (pathologically activated neutrophils) of tumor-bearing mice, the transcription factor STAT5 (likely activated by GM-CSF) upregulated the expression of FATP2, a fatty acid transport protein. FATP2 increased the uptake of arachidonic acid, a precursor for prostaglandin E2 (PGE2). Upregulated PGE2 in PMN-MDSCs mediated immune suppression and tumor growth. Similar results were observed in patients with head and neck, lung, and breast cancer. Selective targeting of PMN-MDSCs via inhibition of FATP2 decreased tumor growth, and combination with anti-CTLA-4 led to tumor rejection in most mice.
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.
Author Info: (1) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. (2) Department of Environmental and Occupational Health, University of Pittsbu
Author Info: (1) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. (2) Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA. (3) Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA. (4) Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA. (5) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. (6) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. (7) University of Pennsylvania School of Medicine, Philadelphia, PA, USA. (8) Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA. (9) Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA. (10) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. (11) University of Pennsylvania School of Medicine, Philadelphia, PA, USA. (12) Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA. (13) Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA, USA. (14) University of Pennsylvania School of Medicine, Philadelphia, PA, USA. (15) Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA. (16) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (17) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (18) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (19) University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (20) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (21) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. (22) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. (23) Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA. (24) Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, USA. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA. Laboratory of Navigational Redox Lipidomics, IM Sechenov Moscow State Medical University, Moskva, Russia. (25) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA. dgabrilovich@wistar.org.
