Myeloid-derived suppressor cells (MDSC) play a major role in immune defects associated with cancer. In cancer, normal myeloid cell differentiation is diverted from its intrinsic pathway of differentiation to mature myeloid cells (dendritic cells (DC), macrophages (M?), and granulocytes) towards differentiation of pathological MDSCs. In mice and humans, currently, two main MDSC populations have been characterized: monocytic MDSCs (M-MDSC) and polymorphonuclear MDSCs (PMN-MDSC). In na?ve mice, the same phenotype defines inflammatory monocytes (Mon) and neutrophils (PMN), respectively. In tumor-bearing (TB) mice, PMN-MDSCs are the prevalent population of MDSC. In cancer patients, MDSC have been isolated from the blood of patients with many different types of cancer. The frequency of MDSC correlates with a poor prognosis and progression in breast and colorectal cancer patients and, recently, was suggested as a biomarker of clinical response to cancer vaccine. Despite their morphologic similarity, PMN-MDSCs and PMNs, as well as M-MDSC and Mon, are functionally and phenotypically different; and MDSC, but not PMN or Mon, are immunosuppressive. Although many aspects of MDSC biology have been clarified in recent years, several fundamental unresolved issues remain. First, how to better distinguish MDSC in cancer patients and TB mice from PMN and Mon? Second, what drives the accumulation of MDSC in cancer? Third, what defines the survival of MDSC and how better to target these cells? Based on our recent preliminary data, we propose a novel concept of pathologic myeloid cell development in cancer. It suggests that, in contrast to physiologic conditions where bone marrow derived Mon differentiate in tissues to M? and DCs, M-MDSC in cancer preferentially differentiate to PMN-MDSC and represent one of the major sources of these cells. Our data suggest that this process is governed by epigenetic silencing of the retinoblastoma (Rb) gene. Our preliminary data demonstrated that PMN-MDSC in TB hosts have a much shorter lifespan than PMN. This effect was mediated by up-regulation of one of the TRAIL receptors (TRAIL-R) on these cells. We propose that pro- inflammatory factors drive up-regulation of TRAIL-R on MDSC. This suggests that TRAIL-R can be a specific target allowing elimination of MDSC, since it is known that normal PMN and other hematopoietic cells are resistant to agonistic TRAIL-R antibody or recombinant TRAIL. In this application we propose to test all these hypotheses in three specific aims.
Specific aim 1. To investigate the role of Rb silencing in the regulation of myeloid cell differentiation in cancer;
Specific aim 2. To study the mechanisms of regulation of MDSC survival in cancer mediated by TRAIL receptors;
Specific aim 3. To study therapeutic targeting of MDSC by triggering TRAIL-receptors;

Public Health Relevance

In this application we will investigate novel concept of differentiation of myeloid-derived suppressor cells in cancer and novel mechanism regulating their survival. The results of this study will not only allow better defining of the biology of thee cells, which are critically important for regulation of immune responses in cancer, but also suggests novel specific mechanisms of their elimination.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wistar Institute
United States
Zip Code
Zhou, Jie; Nefedova, Yulia; Lei, Aihua et al. (2018) Neutrophils and PMN-MDSC: Their biological role and interaction with stromal cells. Semin Immunol 35:19-28
Tang, Chih-Hang; Chang, Shiun; Hashimoto, Ayumi et al. (2018) Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice. Cancer Immunol Res 6:696-710
Tcyganov, Evgenii; Mastio, Jerome; Chen, Eric et al. (2018) Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol 51:76-82
Veglia, Filippo; Perego, Michela; Gabrilovich, Dmitry (2018) Myeloid-derived suppressor cells coming of age. Nat Immunol 19:108-119
Hashimoto, Ayumi; Gao, Chan; Mastio, Jerome et al. (2018) Inhibition of Casein Kinase 2 Disrupts Differentiation of Myeloid Cells in Cancer and Enhances the Efficacy of Immunotherapy in Mice. Cancer Res 78:5644-5655
Kumar, Vinit; Donthireddy, Laxminarasimha; Marvel, Douglas et al. (2017) Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors. Cancer Cell 32:654-668.e5
Dominguez, George A; Condamine, Thomas; Mony, Sridevi et al. (2017) Selective Targeting of Myeloid-Derived Suppressor Cells in Cancer Patients Using DS-8273a, an Agonistic TRAIL-R2 Antibody. Clin Cancer Res 23:2942-2950
Gabrilovich, Dmitry I (2017) Myeloid-Derived Suppressor Cells. Cancer Immunol Res 5:3-8
Condamine, Thomas; Dominguez, George A; Youn, Je-In et al. (2016) Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Sci Immunol 1:
Bronte, Vincenzo; Brandau, Sven; Chen, Shu-Hsia et al. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 7:12150

Showing the most recent 10 out of 55 publications