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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 of the role of tumor microenvironment in 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 who identified the phenomenon of abnormal regulation of DC differentiation and cancer and described 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 2200 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 is 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 niche 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. In recent years the focus of the lab on the emerging new paradigm of combining conventional chemotherapy, radiation therapy, and immunotherapy. 

 

 

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 DILipid 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, GabrilovichDI. 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, GabrilovichDI. 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 DICharacterization 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 DIAntigen-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 DIAutophagy 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 DTherapeutic 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 DEffects 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 DIOxidized 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 DIER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014, 124, 2626-2639.

20 - Condamine T, Gabrilovich DICan 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 DIRegulation 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 DIMyeloid -derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest. 2015 Jul 13:1-9.