Lab In The News
Wistar Researchers Garnered More Than $6M in Funding to Support New Discoveries in Cancer & Infectious Disease
Scientists at The Wistar Institute, an international biomedical research leader in cancer, immunology and infectious diseases, received research funds totaling $6 million between the end of 2017 and the first months of 2018.
Enhancing the Efficacy of Immune Checkpoint Inhibitor Therapy Using a Novel Treatment Combination
A combination of a novel inhibitor of the protein CK2 (Casein kinase 2) and an immune checkpoint inhibitor has dramatically greater antitumor activity than either inhibitor alone, according to research from The Wistar Institute that was published online in Cancer Research.
Wistar Scientists Identified a Cellular Network That “Short Circuits” the Antitumor Effect of Novel Immunotherapy
The discovery accounts for the limited clinical success of CSF-1R blockade therapy and identifies combination therapy to enhance therapeutic effect
The Gabrilovich Laboratory
The Gabrilovich laboratory looks at different aspects of myeloid cell biology and immune responses in cancer. The focus of the lab is on myeloid-derived suppressor cells, dendritic cells and macrophages. They are trying to understand the signaling pathways that are responsible for accumulation and functional defects of immature myeloid cells in cancer. 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 myeloid cell function. In recent years, 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.
Michela Perego, Ph.D.
Filippo Veglia, Ph.D.
Hui Deng, Ph.D.
Taekyoung Kwak, Ph.D.
Jerome Mastio, Ph.D.
Emilio Sanseviero, Ph.D.
Mohit Sehgal, Ph.D.
Evgenii Tcyganov, Ph.D.
Fang Wang, Ph.D.
Sreesha Nambiar Sreedhar
The research of Gabrilovich laboratory is focused on study of myeloid cells in tumor microenvironment, regulation of immune responses and immune suppression in cancer as well as on the development of new effective cancer immunotherapeutics.
Specifically, they are working on several different but closely linked projects:
- Investigation of the mechanism of defective function of professional antigen presenting cells - dendritic cells (DC) in cancer. These cells are responsible for the induction of antitumor immune response. However, their differentiation and function in cancer is severely affected. They are studying the role of cross-presentation in tumor associated immunity and the role of lipid metabolism in negative regulation of cross-presentation;
- Understanding the biology and mechanism of action of myeloid-derived suppressor cells (MDSC) 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. The Gabrilovich laboratory is studying the mechanisms of their expansion and differentiation, specifically focusing on the role of retinoblastoma (Rb) gene in this process. They also investigate the mechanisms of T-cell tolerance induced by MDSC and potential therapeutic approaches to eliminate MDSC in pre-clinical and clinical settings;
- Investigation of the role of ER stress response in pathological function of myeloid cells in cancer. They are studying molecular mechanism regulating ER stress response and its biological consequences for immune suppressive activity of MDSC;
- Investigation of the effect of tumor microenvironment on differentiation and function of myeloid cells including immature myeloid cells, tumor associated macrophages and dendritic cells. They 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 of the role of metabolism in MDSC migration and their contribution to tumor metastases;
- Investigation of the role of reactive oxygen species (ROS) in tumor associated immune defects. They are trying to identify the molecular mechanisms of increased ROS production in myeloid cells in cancer and it potential effect on effector cells;
- The Gabrilovich lab is involved in several clinical trials targeting MDSC in cancer.
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.
He, Y.M., Li, X., Perego, M., Nefedova, Y., Kossenkov, A.V., Jensen, E.A., Kagan, V., Liu, Y.F., Fu, S.Y., Ye, Q.J., Zhou, Y.H., Wei, L., Gabrilovich, D.I., Zhou, J. "Transitory presence of myeloid-derived suppressor cells in neonates is critical for control of inflammation." Nat Med. 2018 Feb;24(2):224-231. doi: 10.1038/nm.4467. Epub 2018 Jan 15.
Veglia, F., Tyurin, V.A., Gabrilovich, D.I., et al. "Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer." Nat Commun. 2017 Dec 14;8(1):2122. doi: 10.1038/s41467-017-02186-9.
Kumar, V., Donthireddy, L., Gabrilovich, D.I., et al. "Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors." Cancer Cell. 2017 Nov 13;32(5):654-668.e5. doi: 10.1016/j.ccell.2017.10.005.
Condamine, T., Dominguez, G.A., Gabrilovich, D.I., et al. "Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients." Sci Immunol. 2016 Aug;1(2). pii: aaf8943. doi: 10.1126/sciimmunol.aaf8943. Epub 2016 Aug 5.
Kumar, V., Cheng, P., Gabrilovich, D.I., et al. "CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation." Immunity. 2016 Feb 16;44(2):303-15. doi: 10.1016/j.immuni.2016.01.014.