Lab In The News
Identification of a Critical Regulator of Immune Suppressive Cells Reveals a Novel Target for Cancer Immunotherapy
Pharmacological block of the FATP2 protein selectively inhibits myeloid-derived suppressor cells and shows antitumor effects in preclinical models.
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 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.
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 (MDSCs), dendritic cells (DCs) and macrophages. They are trying to understand the molecular mechanisms regulating accumulation and function of various populations of 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 endoplasmic reticulum (ER) stress and lipid accumulation in the defective function of DCs and MDSCs in cancer as well as on the mechanisms regulating MDSCs migration to form pre-metastatic niches and activate dormant tumor cells.
Gabrilovich and his group also investigate new immunotherapy strategies in cancer. They are exploring several different approaches, including genetically modified DCs, T cell transfers, checkpoint blockade, and others.
Michela Perego, Ph.D.
Hui Deng, Ph.D.
Shuyu Fu, Ph.D.
Ayumi Hashimoto, Ph.D.
Taekyoung Kwak, Ph.D.
Jocelyn Rivera Ortiz, Ph.D.
Emilio Sanseviero, Ph.D.
Evgenii Tcyganov, Ph.D.
Fang Wang, Ph.D.
Research Assistant Professor
Filippo Veglia, Ph.D.
Sreesha Nambiar Sreedhar
The research in the Gabrilovich laboratory is focused on the study of myeloid cells in the tumor microenvironment, the 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 (DCs) in cancer. These cells are responsible for the induction of antitumor immune response. However, their differentiation and function in cancer is severely affected. The lab is 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 (MDSCs) 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. They also investigate the mechanisms of T-cell tolerance induced by MDSCs and potential therapeutic approaches to eliminate MDSCs in pre-clinical and clinical settings;
- Investigation of the role of the ER stress response in the pathological function of myeloid cells in cancer. The team is studying the molecular mechanism regulating ER stress response and its biological consequences for the immune suppressive activity of MDSCs;
- 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 the tumor milieu;
- Investigation of the role of metabolism in MDSCs migration and their contribution to tumor metastasis;
- Investigation of the role of reactive oxygen species (ROS) in tumor-associated immune defects. The lab is trying to identify the molecular mechanisms of increased ROS production in myeloid cells in cancer and its potential effect on effector cells;
- The Gabrilovich lab is involved in several clinical trials targeting MDSCs in cancer.
Myeloid cells play a major role in the regulation of immune responses. They include professional antigen-presenting cells, DCs, macrophages and MDSCs. Data generated in the Gabrilovich laboratory have demonstrated that differentiation and function of various myeloid cells in cancer are severely affected. Gabrilovich and his team were one of the first labs to identify the phenomenon of abnormal regulation of DC differentiation in 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 DCs are associated with accumulation of immature myeloid cells in tumor-bearing animals and cancer patients. 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, DCs 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 (MDSCs),” which is now widely used to characterize these cells. Since 2007, when the term was introduced by Gabrilovich and colleagues, more than 4000 papers studying these cells were published. Since 2014, Dr. Gabrilovich is included to the list of most highly cited researchers compiled by Clarivate Analytics.
Veglia, F., Tyurin, V.A., Gabrilovich, D.I., et al. "Fatty acid transport protein 2 reprograms neutrophils in cancer." Nature. 2019 May;569(7754):73-78. doi: 10.1038/s41586-019-1118-2. Epub 2019 Apr 17.
Patel, S., Fu, S., Gabrilovich, D.I., et al. "Unique pattern of neutrophil migration and function during tumor progression." Nat Immunol. 2018 Nov;19(11):1236-1247. doi: 10.1038/s41590-018-0229-5. Epub 2018 Oct 15.
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.