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

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

  • Christopher M. Davis Professor
  • Professor and Program Leader, Translational Tumor Immunology Program
  • 215-495-6955, Office
  • dgabrilovich@wistar.org
Summary

The laboratory of Dmitry Gabrilovich focuses on understanding the role of the tumor microenvironment in the regulation of immune responses in cancer and tumor progression with specific emphasis on meyloid cells.  Based on advances in basic research in the lab, they develop new methods of cancer therapy.  

Myeloid cells play a major role in regulation of immune responses. They include professional antigen-presenting cells, dendritic cells (DC), macrophages and myeloid-derived suppressor cells. Data generated in his laboratory have demonstrated that differentiation and function of various myeloid cells in cancer is severely affected. Gabrilovich and his team was one of the first labs to identify the phenomenon of abnormal regulation of DC differentiation and cancer and describe the mechanisms regulating this phenomenon. They proposed several therapeutic strategies to overcome those defects. Some of them are currently being tested in clinical trials. 

Gabrilovich and his group have found that defects in differentiation of DC are associated with accumulation of immature myeloid cells in tumor-bearing animals and patients with cancer. Under normal conditions, these cells represent an intermediate stage of myeloid cell differentiation. In cancer, however, they lose the ability to differentiate into mature myeloid cells, including granulocytes, DC, and macrophages. They become functionally defective and acquire the ability to suppress immune responses. Gabrilovich, together with investigators from other institutions, coined the term “myeloid-derived suppressor cells (MDSC),” which is now widely used to characterize these cells. Since 2007, when the term was introduced by Gabrilovich and colleagues, more than 2800 papers studying these cells were published.

His lab looks at different aspects of immature myeloid cell biology in cancer. First, they are trying to understand the signaling pathways that are responsible for accumulation and functional defects of immature myeloid cells in cancer. These pathways include NF-kB, Jak-STAT, Notch, Wnt, Rb, and others. Second, they are investigating cellular and molecular mechanisms of T-cell suppression and tolerance induced as a result of abnormal differentiation of myeloid cells and abnormal DC function. The main focus of this group is on the role of reactive oxygen species and peroxynitrite in regulation of T-cell function.  His work demonstrates that reactive oxygen species produced by immature myeloid cells in vitro and in tumor-bearing animals in the presence of tumor-derived soluble factors are substantial contributors to the immunosuppression mediated by these cells in cancer.  In recent years, Dr. Gabrilovich has focused on the role of lipid accumulation in the defective function of DCs and MDSC in cancer as well as on the mechanisms regulating MDSC migration to form pre-metastatic niches and activate dormant tumor cells. 

Gabrilovich and his groups also investigate new immune therapy strategies in cancer. They are exploring several different approaches, including genetically modified DCs, T-cell transfers, checkpoint blockade, and others.

 

 

Selected Publications

1 - Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of immune system. Nat. Rev. Immunol. 2009 Mar; 9(3): 162-174.

2 - Zhou J, Cheng P, Youn JI, Cotter MJ, Gabrilovich DI.  Notch and Wnt signaling cooperate in  regulation of dendritic cell differentiation. Immunity. 2009, 30, 845-859.

3 - Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, Meyer C, Becerra CR, Fishman M, Antonia S, Sporn MB, Liby KT, Rawal B, Lee JH, Gabrilovich DI. Anti-inflammatory triterpenoid blocks immune suppressive function of myeloid-derived suppressor cells and improves immune response in cancer. Clin Cancer Res.  2010; 16(6):1812-1823.    

4 - Ramakrishnan R, Assudani D, Nagaraj S, Hunter T, Cho HI, Antonia S, Altiok S, Celis E, Gabrilovich DI. Mechanism of combined effect of cancer immunotherapy and chemotherapy. J Clin. Invest. 2010, 120: 1111-1124.

5 - Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, Corzo A, Cho HI, Celis E, Lennox B, Knight SC, Padhya T, McCaffrey TV, McCaffrey JC, Antonia S, Fishman M, Ferris RL, Kagan VE, Gabrilovich DI. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 2010; 16, 880-886.

6 - Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, Cho HI, Celis E., Quiceno DG, Padhya T,McCaffrey TV, McCaffrey JC, Gabrilovich DI. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 2010, 207, 2439-2453.

7 - Condamine T. and Gabrilovich DI. Molecular mechanisms of MDSC differentiation. Trends in Immunol. 2011 Jan;32(1):19-25.

8 - Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, Gabrilovich DI. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells. J. Clin. Invest. 2011, 121(10):4015-29.

9 - Youn JI, Collazo M, Shalova IN, Biswas SK, Gabrilovich DI. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc Biol. 2012, 91, 167-181.

10 - Nagaraj S, Nelson A, Youn JI, Cheng P, Quiceno D, Gabrilovich DI. Antigen-Specific CD4+ T Cells Regulate Function of Myeloid-Derived Suppressor Cells in Cancer via Retrograde MHC Class II Signaling. Cancer Res. 2012; 72, 928-938.

11 - Gabrilovich DI, Ostrand-Rosenberg S., Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 2012, 12, 253-268.

12 - Ramakrishnan R, Huang C, Cho HI, Lloyd M, Johnson J, Ren X, Altiok S, Sullivan D, Weber J, Celis E, Gabrilovich DI. Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy. Cancer Res. 2012; 72, 5483-5493.

13 - Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, Villagra A, Antonia S, McCaffrey JC, Fishman M, Sarnaik A, Horna P, Sotomayor E, Gabrilovich DI. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat. Immunol. 2013, 14: 211-220.

14 - Iclozan C, Antonia S, Chiappori A, Chen DT, Gabrilovich D. Therapeutic regulation of myeloid-derived suppressor cells and immune response to cancer vaccine in patients with extensive stage small cell lung cancer. Cancer Immunol Immunother2013;62(5):909-18.

15 - Talmadge EJ, Gabrilovich DI. History of myeloid-derived suppressor cells. Nat. Rev. Cancer. 2013, 10:739-752.

16 - Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, Epling-Burnette P, Van Bijnen S, Dolstra H, Cannon J, Youn JI, Donatelli SS, Qin D, De Witte T, Tao J, Wang H, Cheng P, Gabrilovich DI*, List A*, Wei S*. Microenvironment induced myelodysplasia mediated by myeloid-derived suppressor cells. J. Clin. Invest. 2013123(11):4595-611.

17 - Cheng P, Kumar V, Liu H, Youn JI, Fishman M, Sherman S, Gabrilovich D. Effects of Notch signaling on regulation of myeloid cell differentiation in cancer. Cancer Res. 2014 74(1):141-152.

18 - Ramakrishnan R, Tuyrin VA, Veglia F, Condamine T, Amoscato A, Mohammadyani D, Johnson JJ, Min Zhang L, Klein-Seetharaman J, Celis E, Kagan VE, Gabrilovich DI. Oxidized Lipids Block Antigen Cross-Presentation by Dendritic Cells in Cancer. J Immunol. 2014, 192: 2920-2931.

19 - Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, El-Deiry WS, Winograd R, Vonderheide RH, English NR, Knight SC, Yagita H, McCaffrey JC, Antonia S, Hockstein N, Witt R, Masters G, Bauer T, Gabrilovich DI. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014, 124, 2626-2639.

20 - Condamine T, Gabrilovich DI. Can the Suppressive Activity of Myeloid-Derived Suppressor Cells Be "Chop"ped? Immunity. 2014; 41(3):341-2.

21 - Condamine T, Ramachandran I, Youn JI, Gabrilovich DI. Regulation of tumor metastasis by myeloid-derived suppressor cells. Annu Rev Med. 2015;66:97-110.

22 - Ortiz M, Kumar V, Martner A, Mony S, Donthireddy L, Condamine T, Seykora J, Knight S, Malietzis G, Lee G, Moorghen M, Lenox B, Luetteke N, Celis E, Gabrilovich D. Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17 producing CD4+ T cells. J Exp Med. 2015, 212, 351-367.

23 - Marvel D, Gabrilovich DI. Myeloid -derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015 Jul 13:1-9.

24 - Gabrilovich D, Nefedova Y. ROR1C Regulates Differentiation of Myeloid-Derived Suppressor Cells. Cancer Cell. 2015 Aug 10;28(2):147-9.

25 - Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol. 2015 Dec;98(6):913-22

26- Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol. 2016 Mar;37(3):208-20

27- Kumar V, Cheng P, Condamine T, Mony S, Languino LR, McCaffrey JC, Hockstein N, Guarino M, Masters G, Penman E, Denstman F, Xu X, Altieri DC, Du H, Yan C, Gabrilovich DI. CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. Immunity. 2016 Feb 16;44(2):303-15

28- Bronte V, Brandau S, Chen SH, Colombo MP, Frey AB, Greten TF, Mandruzzato S, Murray PJ, Ochoa A, Ostrand-Rosenberg S, Rodriguez PC, Sica A, Umansky V, Vonderheide RH, Gabrilovich DI. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun. 2016 Jul 6;7:12150.

29-Dominguez G, Condamine TC, Mony S, Hashimoto A, Wang F, Liu Q, Forero A, Bendell JC, Witt R, Hockstein N, Kumar P, Gabrilovich D. Selective targeting of myeloid-derived suppressor cells in cancer patients using DS-8273a, an agonistic TRAIL-R2 antibody. Clin Cancer Res. 2016 Dec 13

30 - Caino MC, Seo JH, Aguinaldo A, Wait E, Bryant KG, Kossenkov AV, Hayden JE, Vaira V, Morotti A, Ferrero S, Bosari S, Gabrilovich DI, Languino LR, Cohen AR, Altieri DC. A neuronal network of mitochondrial dynamics regulates metastasis. Nat Commun. 2016 Dec 19;7:13730

31- Gabrilovich DI. Myeloid-Derived Suppressor Cells. Cancer Immunol Res. 2017 Jan;5(1):3-8.