Fatty acid transport protein 2 reprograms neutrophils in cancer
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...
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| Veröffentlicht in: | Nature (London) 2019-05, Vol.569 (7754), p.73-78 |
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| creator | Veglia, Filippo Tyurin, Vladimir A. Blasi, Maria De Leo, Alessandra Kossenkov, Andrew V. Donthireddy, Laxminarasimha To, Tsun Ki Jerrick Schug, Zach Basu, Subhasree Wang, Fang Ricciotti, Emanuela DiRusso, Concetta Murphy, Maureen E. Vonderheide, Robert H. Lieberman, Paul M. Mulligan, Charles Nam, Brian Hockstein, Neil Masters, Gregory Guarino, Michael Lin, Cindy Nefedova, Yulia Black, Paul Kagan, Valerian E. Gabrilovich, Dmitry I. |
| description | 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.
The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E
2
. |
| doi_str_mv | 10.1038/s41586-019-1118-2 |
| format | Article |
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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.
The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E
2
.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-019-1118-2</identifier><identifier>PMID: 30996346</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/106 ; 13/31 ; 13/44 ; 42/41 ; 45/91 ; 631/250/580 ; 631/67/327 ; 64/60 ; Aged ; Animals ; Arachidonic acid ; Arachidonic Acid - metabolism ; Bone marrow ; Cancer ; Cancer treatment ; Cell activation ; Clonal deletion ; Colony-stimulating factor ; Dendritic cells ; Dinoprostone - metabolism ; Fatty Acid Transport Proteins - antagonists & inhibitors ; Fatty Acid Transport Proteins - metabolism ; Fatty acids ; Fatty Acids - metabolism ; Female ; Gene expression ; Genomes ; Granulocyte-macrophage colony stimulating factor ; Health aspects ; Humanities and Social Sciences ; Humans ; Immune checkpoint ; Immune response ; Immunosuppressive agents ; Leukocytes (neutrophilic) ; Lipid Metabolism ; Lipids ; Macrophage colony stimulating factor ; Macrophages ; Male ; Medical schools ; Mice ; Middle Aged ; multidisciplinary ; Neoplasms - metabolism ; Neoplasms - pathology ; Neutrophils ; Neutrophils - metabolism ; Neutrophils - pathology ; Pharmacology ; Physiological aspects ; Prostaglandin E2 ; Prostaglandins ; Protein transport ; Proteins ; Science ; Science (multidisciplinary) ; Stat5 protein ; STAT5 Transcription Factor - metabolism ; Suppressor cells ; Transcription activation ; Transport ; Transport proteins ; Triglycerides ; Tumors ; Unsaturated fatty acids</subject><ispartof>Nature (London), 2019-05, Vol.569 (7754), p.73-78</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 2, 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c720t-592c84f846faf17b7fefde5434b5e130097e6b626be5d5ac4eba5e961f3538293</citedby><cites>FETCH-LOGICAL-c720t-592c84f846faf17b7fefde5434b5e130097e6b626be5d5ac4eba5e961f3538293</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,782,786,27931,27932</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30996346$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Veglia, Filippo</creatorcontrib><creatorcontrib>Tyurin, Vladimir A.</creatorcontrib><creatorcontrib>Blasi, Maria</creatorcontrib><creatorcontrib>De Leo, Alessandra</creatorcontrib><creatorcontrib>Kossenkov, Andrew V.</creatorcontrib><creatorcontrib>Donthireddy, Laxminarasimha</creatorcontrib><creatorcontrib>To, Tsun Ki Jerrick</creatorcontrib><creatorcontrib>Schug, Zach</creatorcontrib><creatorcontrib>Basu, Subhasree</creatorcontrib><creatorcontrib>Wang, Fang</creatorcontrib><creatorcontrib>Ricciotti, Emanuela</creatorcontrib><creatorcontrib>DiRusso, Concetta</creatorcontrib><creatorcontrib>Murphy, Maureen E.</creatorcontrib><creatorcontrib>Vonderheide, Robert H.</creatorcontrib><creatorcontrib>Lieberman, Paul M.</creatorcontrib><creatorcontrib>Mulligan, Charles</creatorcontrib><creatorcontrib>Nam, Brian</creatorcontrib><creatorcontrib>Hockstein, Neil</creatorcontrib><creatorcontrib>Masters, Gregory</creatorcontrib><creatorcontrib>Guarino, Michael</creatorcontrib><creatorcontrib>Lin, Cindy</creatorcontrib><creatorcontrib>Nefedova, Yulia</creatorcontrib><creatorcontrib>Black, Paul</creatorcontrib><creatorcontrib>Kagan, Valerian E.</creatorcontrib><creatorcontrib>Gabrilovich, Dmitry I.</creatorcontrib><title>Fatty acid transport protein 2 reprograms neutrophils in cancer</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>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.
The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E
2
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Database</collection><collection>Engineering Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Earth, Atmospheric & Aquatic Science Database</collection><collection>Materials Science Collection</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest One Psychology</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>ProQuest Central Basic</collection><collection>University of Michigan</collection><collection>Genetics Abstracts</collection><collection>SIRS Editorial</collection><collection>Environment Abstracts</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Veglia, Filippo</au><au>Tyurin, Vladimir A.</au><au>Blasi, Maria</au><au>De Leo, Alessandra</au><au>Kossenkov, Andrew V.</au><au>Donthireddy, Laxminarasimha</au><au>To, Tsun Ki Jerrick</au><au>Schug, Zach</au><au>Basu, Subhasree</au><au>Wang, Fang</au><au>Ricciotti, Emanuela</au><au>DiRusso, Concetta</au><au>Murphy, Maureen E.</au><au>Vonderheide, Robert H.</au><au>Lieberman, Paul M.</au><au>Mulligan, Charles</au><au>Nam, Brian</au><au>Hockstein, Neil</au><au>Masters, Gregory</au><au>Guarino, Michael</au><au>Lin, Cindy</au><au>Nefedova, Yulia</au><au>Black, Paul</au><au>Kagan, Valerian E.</au><au>Gabrilovich, Dmitry I.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fatty acid transport protein 2 reprograms neutrophils in cancer</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2019-05</date><risdate>2019</risdate><volume>569</volume><issue>7754</issue><spage>73</spage><epage>78</epage><pages>73-78</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><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.
The lipid transporter FATP2 reprograms neutrophils to polymorphonuclear myeloid-derived suppressor cells by mediating the uptake of arachidonic acid and promoting the synthesis of prostaglandin E
2
.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30996346</pmid><doi>10.1038/s41586-019-1118-2</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2019-05, Vol.569 (7754), p.73-78 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_journals_2224909285 |
| source | MEDLINE; Nature; Alma/SFX Local Collection |
| subjects | 13 13/106 13/31 13/44 42/41 45/91 631/250/580 631/67/327 64/60 Aged Animals Arachidonic acid Arachidonic Acid - metabolism Bone marrow Cancer Cancer treatment Cell activation Clonal deletion Colony-stimulating factor Dendritic cells Dinoprostone - metabolism Fatty Acid Transport Proteins - antagonists & inhibitors Fatty Acid Transport Proteins - metabolism Fatty acids Fatty Acids - metabolism Female Gene expression Genomes Granulocyte-macrophage colony stimulating factor Health aspects Humanities and Social Sciences Humans Immune checkpoint Immune response Immunosuppressive agents Leukocytes (neutrophilic) Lipid Metabolism Lipids Macrophage colony stimulating factor Macrophages Male Medical schools Mice Middle Aged multidisciplinary Neoplasms - metabolism Neoplasms - pathology Neutrophils Neutrophils - metabolism Neutrophils - pathology Pharmacology Physiological aspects Prostaglandin E2 Prostaglandins Protein transport Proteins Science Science (multidisciplinary) Stat5 protein STAT5 Transcription Factor - metabolism Suppressor cells Transcription activation Transport Transport proteins Triglycerides Tumors Unsaturated fatty acids |
| title | Fatty acid transport protein 2 reprograms neutrophils in cancer |
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