Dmitry I. Gabrilovich, M.D., Ph.D.
Dmitry I. Gabrilovich, M.D., Ph.D.
- Christopher M. Davis Professor
- Professor, Tumor Microenvironment and Metastasis Program
- 215-495-6955, Office
The laboratory of Dmitry Gabrilovich focuses on a number of methods that tumors use to suppress the immune system, and on the development of new, effective methods of immune therapy of cancer.
Gabrilovich investigates abnormalities in the function of various myeloid cells. These cells play a major role in regulation of immune responses. One group of cells is professional antigen-presenting cells, dendritic cells (DC). These cells are responsible for induction of the anti-tumor immune response. Data generated in his laboratory have demonstrated that their differentiation and function are severely affected in cancer. Gabrilovich and his team have identified the mechanisms of these abnormalities and 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 600 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.
Gabrilovich and his groups also investigate new tumor vaccines. They are exploring several different approaches, including genetically modified DCs. In recent years the focus of the lab on the emerging new paradigm of combining conventional chemotherapy, radiation therapy, and immunotherapy.
1 - Liu H, Zhou J, Cheng P, Ramachandran I, Nefedova Y, Gabrilovich DI. Regulation of Dendritic Cell Differentiation in Bone Marrow during Emergency Myelopoiesis. J Immunol. 2013 Aug 15;191(4):1916-26. 23833236
2- Nagaraj S, Youn JI, Gabrilovich DI. Reciprocal Relationship between Myeloid-Derived Suppressor Cells and T Cells. J Immunol. 2013 Jul 1;191(1):17-23. 23794702
3 - Ramachandran IR, Martner A, Pisklakova A, Condamine T, Chase T, Vogl T, Roth J, Gabrilovich D, Nefedova Y. Myeloid-derived suppressor cells regulate growth of multiple myeloma by inhibiting T cells in bone marrow. J Immunol. 2013 Apr;190(7):3815-3823. 23460744.
4 - Ramakrishnan R, Gabrilovich DI. The role of mannose-6-phosphate receptor and autophagy in influencing the outcome of combination therapy. Autophagy. 2013 Apr;9(4):615-616. 23324210.
5 - Ramakrishnan R, Gabrilovich DI. Novel mechanism of synergistic effects of conventional chemotherapy and immune therapy of cancer. Cancer Immunol Immunother. 2013 Mar;62(3):405-410. 23423351.
6 - Gabrilovich DI. Applying pressure on macrophages. Immunity. 2013 Feb;38(2):205-206. 23438819.
7 - 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 Jan;14(3):211-220. 23354483.
8 - Wang D, Yu Y, Haarberg K, Fu J, Kaosaard K, Nagaraj S, Anasetti C, Gabrilovich D, Yu XZ. Dynamic Change and Impact of Myeloid-Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice. Biol Blood Marrow Transplant. 2013 Jan. 23376089.
9 - 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 Nov;72(21):5483-5493. 22942258.
10 - Lu T, Gabrilovich DI. Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment. Clin Cancer Res. 2012 Sep;18(18):4877-4882. 22718858.