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Dmitry Gabrilovich, M.D., Ph.D.

Identification of a Critical Regulator of Immune Suppressive Cells Reveals a Novel Target for Cancer Immunotherapy 

PHILADELPHIA — (April 17, 2019) — Wistar scientists have identified a critical regulator of the function of myeloid derived suppressive cells (MDSCs), opening new opportunities for specific therapeutic targeting of these cells to inhibit tumor growth and enhance the anticancer activity of other immunotherapies. Study results were published online in Nature.

MDSCs are a bone marrow-derived cell population that becomes pathologically activated in cancer patients and inhibits the body’s antitumor immune response. They are associated with poor prognosis and resistance to immunotherapy. The mechanisms responsible for conversion of these cells into immune suppressive cells are not well defined.

“MDSCs have emerged as fundamental players in the fight of our immune system against cancer and the success of certain therapies,” said senior author Dmitry I. Gabrilovich, M.D., Ph.D., Christopher M. Davis Professor and program leader of the Immunology, Microenvironment and Metastasis Program at Wistar. “We need to better define how these cells work and what pathways are important, so that we can devise strategies to keep them at bay. Our study represents an important step forward in that direction.”

Gabrilovich and collaborators delved into MDSC lipid metabolism because the accumulation of lipids has been shown in several immune cells in the tumor microenvironment. They found a specific role for a protein called FATP2, which mediates the intake of fatty acids. 

They compared MDSCs isolated from mice carrying different tumor types with the corresponding cell population in healthy mice and observed a much higher expression of the gene that encodes for FATP2, specifically in polymorphonuclear MDSCs (PMN-MDSCs), which are the immunosuppressive counterpart of neutrophils. They showed that FATP2 mediates the immunosuppressive activity of PMN-MDSCs.

At the molecular level, the team found that FATP2 selectively allows for the accumulation of a type of fatty acid called arachidonic acid, which is needed for the cells to make prostaglandin E2 (PGE2), a potent inflammatory molecule that is also implicated in the immunosuppressive activity of MDSCs in cancer. They also characterized the signaling pathway that activates transcription of the FATP2 gene in PMN-MDSCs. 

Importantly, the observations obtained in the mouse models were recapitulated in PMN-MDSCs isolated from cancer patients. These cells have a higher lipid content and higher expression of FATP2 than the counterpart isolated from healthy donors. 

“The obvious next step in our research was to verify whether FATP2 was a good candidate from a therapeutic standpoint,” said Filippo Veglia, Ph.D., a research assistant professor in the Gabrilovich Lab and first author on the study. “We were excited to find that a selective inhibitor of FATP2 called lipofermata caused a significant delay of tumor growth in mice.” 

Researchers confirmed this effect was specifically due to activation of the immune system, as it was not observed in immunodeficient mice and after depletion of CD8+ T cells, the cells in charge of destroying the tumor. The antitumor effect was even stronger when lipofermata was given in combination with other immunotherapeutic agents — while the single treatments slowed down tumor progression, most of the mice that received the combined treatment completely rejected the tumors.
Gabrilovich and colleagues identified a critical regulator of the function of PMN-MDSCs and described pharmacological inhibition of FATP2 as a novel and specific therapeutic strategy to block the immunosuppressive activity of these cells and enhance the effect of cancer therapy. 

Co-authors: Alessandra De Leo, Andrew Kossenkov, Laxminarasimha Donthireddy, Zach Schug, Subhasree Basu, Fang Wang, Maureen E. Murphy, Paul M. Lieberman, Cindy Lin, and Yulia Nefedova from Wistar; Vladimir A. Tyurin and Valerian E. Kagan from the University of Pittsburgh; Maria Blasi from Duke University School of Medicine; Tsun Ki Jerrick To, Emanuela Ricciotti, Gregory Masters, and Robert H. Vonderheide from University of Pennsylvania School of Medicine; Concetta DiRusso and Paul Black from University of Nebraska; Charles Mulligan, Brian Nam, Neil Hockstein, and Michael Guarino from Helen F Graham Cancer Center at Christiana Care Health System. 

Work supported by: National Institutes of Health (NIH) grants CA R01CA165065 and AI110485. Core support for Wistar was provided by Cancer Center Support Grant P30CA010815. 

Publication information: Fatty acid transporter 2 reprograms neutrophils in cancer, Nature (2019). Advance online publication.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

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