University of South Florida

Cancer Biology Ph.D. Program at the

Dmitry I. Gabrilovich M.D., Ph.D. Professor in the Department of Oncologic Sciences Member-in-Residence of the Moffitt Cancer Center E-mail:Dmitry.Gabrilovich@moffitt.org Phone: (813)745-6863

Training
M.D. Kabardino-Balkarian State University (USSR), 1984
Ph.D. in Immunology, Central Institute for Epidemiology, Moscow, Russia. 1989
Postdoctoral fellow, Imperial College, London, UK in immunology and dendritic cell biology 1992-1994
Postdoctoral fellow, U.T. Southwestern Medical Center, Dallas, TX. in tumor immunology and molecular biology 1994-1996

Research Interests
Research of our laboratory is focused on understanding the mechanisms of tumor-associated immunosuppression as well as on the development of new effective cancer vaccines. Specifically, they are working on several different but closely linked projects.

• Investigation of differentiation of professional antigen presenting cells - dendritic cells (DC). These cells are responsible for induction of antitumor immune response. However, their differentiation and function in cancer is severely affected. We are studying signal transduction mechanisms involved in DC differentiation: the role of transcriptional regulator Notch-1, transcription factors NF-kB, and JAK-STAT pathway.
• Another direction of the research involves understanding the biology and mechanism of action of immunosuppressive immature myeloid cells that accumulate in cancer patients and tumor-bearing mice. These cells are shown to be one of the major factors in the development of tumor non-responsiveness. Our laboratory is studying the mechanism of T-cell tolerance induced by these cells including role of different factors, mechanisms of these cells differentiation and potential therapeutic approaches to eliminate these immature myeloid cells in pre-clinical settings.
• Investigation of the effect of tumor microenvironment on differentiation and function of myeloid cells including immature myeloid cells, tumor associated macrophages and dendritic cells. We are studying the role of different factors (tumor endothelium, cytokines, hypoxia) that could be responsible for abnormal differentiation and function of these cells in tumor milieu.
• Investigation the role of reactive oxygen species (ROS) in tumor associated immune defects. We are trying to identify the molecular mechanisms of increased ROS production in myeloid cells in cancer and it potential effect on effector cells.

Another large part of our research is the development of new tumor vaccines. We are exploring several different approaches including genetically modified dendritic cells and the combination of apoptosis-inducing therapy and immunotherapy.

• Currently we have survivin based vaccine in pre-clinical development.
• We are currently conducting and monitoring several clinical trials based on p53 transduced DCs in patients with small cell lung cancer and breast cancer.
• We are conducting clinical trial of intratumoral administration of DCs in patients with prostate cancer in combination with local radiation.

Several trials are performed to assess the effect of different approaches to improve differentiation and function of myeloid cells in cancer patients. They include trials of all-trans retinoic acid (ATRA) and anti-VEGF therapy (avastin and VEGF-trap).

Search for publications by:   
This search will be conducted at the US National Library of Medicine (NLM) and PubMed.

Selected Publications (since 2003)

Nefedova Y., Nagaraj S., Rosenbauer A., Muro-Cacho C., Sebti S.M., Gabrilovich D.I. Regulation of dendritic cell differentiation and antitumor immune response in cancer by pharmacological selective inhibition of the Jak2/STAT3 pathway. Cancer Res. 2005 (in press)

Nefedova Y., Cheng P., Gilkes D., Blaskovich M., Beg A.A., Sebti S.M., Gabrilovich D.I. Activation of dendritic cells via inhibition of Jak2/STAT3 signaling. J. Immunol. 2005 (in press).

Sergei Kusmartsev, Srinivas Nagaraj, Dmitry I. Gabrilovich. Tumor associated CD8+ T-cell tolerance induced by bone marrow derived immature myeloid cells. J. Immunol. 2005 (in press).

Kusmartsev S., Gabrilovich D.I. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol. Immunoth. 2005 (in press)

Plescia 1 J., Salz 1 W. , Xia 1 F. , Pennati M., Zaffaroni N., Daidone MG., Meli M., Dohi T., Fortugno P. , Nefedova Y., Gabrilovich DI., Colombo G. , Altieri DC. Rational design of shepherdin, a novel anti-cancer agent. Cancer Cell 2005, 7, 457-468

Maroof A., English N., Bedford P., Gabrilovich D. Knight S. Developing dendritic cells become “lacy” cells, packed with fat and glycogen. Immunology 2005, 113, 473-485

Kusmartsev S. and Gabrilovich D.I. STAT1 Signaling Regulates Tumor-Associated Macrophages-mediated T-cell deletion. J. Immunol. 2005, 174, 4880-4891

Gabrilovich  D . Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nature Review Immunol . 2004, 4, 941-952

Wang T., Niu G., Kortylewski, M., Burdelya L., Shain K., Zhang S., Bhattacharya R ., Gabrilovich D, Heller R., Coppola D., Dalton W., Jove R., Pardoll D., Yu H. Regulation of the innate and adaptive immune responses by STAT-3 signaling in tumor cells. Nature Med. 2004, 10, 48-54

Nefedova Y., Cheng P., Alsina M., Dalton W.S., Gabrilovich D.I. Notch-1 signaling is involved in bone marrow stroma mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 2004; 103, 3503-3510

Kusmartsev S., Nefedova Y., Yoder D., Gabrilovich D.I. Antigen-specific Inhibition of CD8 + T cell Response by Immature Myeloid Cells in Cancer is Mediated by Reactive Oxygen Species. J. Immunol. 2004, 172: 989-999

Nefedova Y., Huang M., Kusmartsev S., Bhattacharya R., Cheng P., Salup R., Jove R., Gabrilovich D.I. Hyperactivation of STAT3 is involved in abnormal differentiation of dendritic cells in cancer. J. Immunol. 2004, 172, 464-474

Cheng P., Nefedova Y. , Miele L., Osborne B.A., Gabrilovich D.I. Notch signaling is necessary but not sufficient for differentiation of dendritic cells. Blood, 2003, 102:3980-3988.

Pisarev V., Yu B., Salup R., Sherman S., Altieri D.C., Gabrilovich D. Full-length dominant negative survivin for cancer immunotherapy. Clin. Cancer Res. 2003 9(17): 6523-6533

Gabrilovich D.I. and Pisarev V.V. Tumor escape from immune response: mechanisms and targets of activity . Current Drug Targets 2003, 4, 525-536

Kusmartsev S. and Gabrilovich D. I. Inhibition of myeloid cell differentiation in cancer: the role of reactive oxygen species. J. Leuk. Biol. 2003 74: 186-196

Kusmartsev S., Cheng F., Yu B., Nefedova Y., Sotomayor E., Lush R., Gabrilovich D.I. All-trans-retinoic acid eliminates immature myeloid cells from tumor-bearing mice and improves the effect of vaccination. Cancer Res. 2003, 63, 4441-4449.

Ohm J.E., Gabrilovich D.I., Kisseleva E., Carbone D.P. VEGF inhibits T cell development and may contribute to tumor-induced immuneosuppression. Blood 2003, 101: 4878-4886

Yu B., Kusmartsev S., Cheng F., Paolini M., Nefedova Y., Sotomayor E., Gabrilovich DI. Effective combination of chemotherapy and dendritic cell administration in treatment of advanced stage experimental breast cancer. Clin. Cancer Res. 2003, 9: 285-294