The persistence of cancer cells within an immune competent host occurs in part due to the suppression of the immune response, particularly of cytotoxic T lymphocytes (CTLs). This suppression may be caused by myeloid-derived suppressor cells, or MDSCs. MDSC accumulation is often seen in human cancer patients and tumor-bearing mice, particularly in lymphoid tissues including spleen, blood, and bone marrow. Cancer cells may use deregulated myelopoiesis and resultant MDSC accumulation as a mechanism of suppressing CTL-induced cytotoxicity, evading immune surveillance, and promoting tumor growth. The dynamic interactions between CTLs and MDSCs thereby determine whether cancer will regress or progress. Interferon Regulatory Factor 8 (IRF8) is a key transcription factor that regulates multiple immune cell processes, including immune cell lineage, particularly myeloid cell lineage differentiation. One key phenotype of IRF8 null mice is accumulation of MDSCs that phenotypically and functionally resemble tumor- induced MDSCs. In addition, IRF8 deficiency also impairs CTL differentiation in response to cytokine signaling under physiological conditions. IRF8 is thus a key regulator of both MDSCs and CTLs. In our preliminary studies, we observed that although IRF8 null mice accumulate MDSCs, surprisingly, mice with IRF8 deficiency only in myeloid cells do not present with significant MDSC accumulation. Instead, mice with IRF8 deficiency only in T cells accumulate MDSCs through a GM-CSF-dependent mechanism. Based on our preliminary observations, we hypothesize that IRF8 controls myelopoiesis through a cell-extrinsic mechanism and regulates CTL differentiation through a cell-intrinsic mechanism, thereby inhibiting MDSC suppressive activity and promoting anti-tumor CTL immunity. To test our hypothesis, we will investigate the following aims: 1) determine if IRF8 silencing promotes tumor persistence-including allograft tumor growth- through MDSC accumulation; and 2) test whether IRF8 is an essential regulator of antigen- specific CTL activation and differentiation in vivo, and if so, whether this regulation occurs in aT cell receptor (TCR) - dependent mechanism. Successful completion of this research project has the potential to develop an IRF8 mechanism-based therapy to control the interactions between MDSCs and CTLs, thereby strengthening CTL anti-cancer immunity in human cancer immunotherapy.

Public Health Relevance

Successful completion of this research project has great potential to develop an IRF8 mechanism-based therapy to control the interactions between MDSCs and CTLs, thereby strengthening CTL anti-cancer immunity to increase the efficacy of human cancer immunotherapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Gondre-Lewis, Timothy A
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Georgia Regents University
Schools of Medicine
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Redd, Priscilla S; Ibrahim, Mohammed L; Klement, John D et al. (2017) SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells. Cancer Res 77:2834-2843
Paschall, Amy V; Yang, Dafeng; Lu, Chunwan et al. (2016) CD133+CD24lo defines a 5-Fluorouracil-resistant colon cancer stem cell-like phenotype. Oncotarget 7:78698-78712
Coe, Genevieve L; Redd, Priscilla S; Paschall, Amy V et al. (2016) Ceramide mediates FasL-induced caspase 8 activation in colon carcinoma cells to enhance FasL-induced cytotoxicity by tumor-specific cytotoxic T lymphocytes. Sci Rep 6:30816
Simon, Priscilla S; Bardhan, Kankana; Chen, May R et al. (2016) NF-?B functions as a molecular link between tumor cells and Th1/Tc1 T cells in the tumor microenvironment to exert radiation-mediated tumor suppression. Oncotarget 7:23395-415
Paschall, Amy V; Liu, Kebin (2016) An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis. J Vis Exp :