Among processes believed to impede the antitumor immune response is the emergence of myeloid cell populations during tumor growth, termed myeloid-derived suppressor cells (MDSC). These immune suppressing cells are distinguished from other myeloid subsets based on their characteristic expression of both CD11b and Gr-1 cell surface markers. Although considerable interest has been dedicated to understanding how MDSC inhibit antitumor immune mechanisms, much less is known regarding the molecular events that govern their development to begin with. Thus, the proposed research will test a novel hypothesis by which these CD11b+Gr-1+ MDSC develop, one which reflects a new functional role for interferon regulatory factor-8 (IRF-8) in tumor immunology. Previous key studies have revealed an essential role for IRF-8, a member of the IRF family of transcription factors, in regulating normal myelopoiesis. The impact of IRF-8 in myelopoiesis has been clearly illuminated by alteration of the gene in mouse models. IRF-8 deficiency leads to myeloproliferative disorders. Collectively, these findings indicate that IRF-8 loss or down-regulation has profound pathologic consequences on myelo-monocytic development and differentiation. Therefore, the primary objective of this proposal is to determine the causal link between IRF-8 expression and CD11b+Gr-1+ MDSC generation, which conceptually may be analogous to the aberrant myelopoiesis observed in IRF-8 null mice. The central hypothesis is that IRF-8 functions to block tumor-induced MDSC development and acquisition of their pro-tumorigenic activities. It is further hypothesized that the neoplastic process alters IRF-8 levels of myeloid progenitors through the inappropriate production and action of certain tumor-derived myelopoietic growth factors. Based on new preliminary data in our tumor models, we have identified abundant levels of G-CSF as a putative tumor-derived factor of MDSC generation. Thus, tumor-induced IRF-8 down-regulation by G-CSF or other STAT3-activating cytokines may underlie a novel pathway for MDSC development. Guided by our recently published data that IRF-8 levels are strongly reduced in, and inversely correlated with, the generation of tumor-induced MDSC, the central hypothesis will be tested by pursuing three specific aims in mouse models: two will be mechanistic and one will be therapeutic in scope: 1) Determine the causal link between IRF-8 expression and MDSC development;2) Identify tumor-induced mechanisms that drive IRF-8 down-regulation and the resultant production of MDSC;and 3) To determine whether blocking MDSC development through IRF-8 over-expression will enhance immunotherapy efficacy. The proposed research will enhance knowledge of the host-tumor interaction and, thus, provide the framework to explore the prognostic or therapeutic significance of elements of this new molecular pathway in cancer clinical settings.

Public Health Relevance

Myeloid-derived suppressor cells (MDSC) are a recently discovered population of white blood cells that accumulate in patients with certain types of solid cancers and are thought to embody a significant barrier to an effective anti-cancer immune response. MDSC are typically identified by their unique expression of two cell surface markers, known as CD11b and Gr-1. Although much interest has been devoted to understanding mechanisms by which MDSC block immunity, much less is known regarding the processes that regulate their development. Our research will explore the concept that these cells arise because cancer cells cause a profound alteration in a 'master gene', called interferon regulatory factor-8 (IRF-8) that is essential for controlling fundamental properties of the myeloid cell family and preventing the generation of MDSC. This work will advance our understanding of mechanisms of immune suppression, and will be highly relevant to cancer and the design of novel prognostic or therapeutic oncologic options.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA140622-04S1
Application #
8745184
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Muszynski, Karen
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
4
Fiscal Year
2014
Total Cost
$52,545
Indirect Cost
$21,046
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Abrams, Scott I (2017) Editorial: The rebirth of myeloid-derived suppressor cells: from adversary in cancer to ally in reproductive health. J Leukoc Biol 101:1079
Twum, Danielle Y F; Burkard-Mandel, Lauren; Abrams, Scott I (2017) The Dr. Jekyll and Mr. Hyde complexity of the macrophage response in disease. J Leukoc Biol 102:307-315
Netherby, Colleen S; Abrams, Scott I (2017) Mechanisms overseeing myeloid-derived suppressor cell production in neoplastic disease. Cancer Immunol Immunother 66:989-996
Minderman, Hans; Maguire, Orla; O'Loughlin, Kieran L et al. (2017) Total cellular protein presence of the transcription factor IRF8 does not necessarily correlate with its nuclear presence. Methods 112:84-90
Bucsek, Mark J; Qiao, Guanxi; MacDonald, Cameron R et al. (2017) ?-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Res 77:5639-5651
Netherby, Colleen S; Messmer, Michelle N; Burkard-Mandel, Lauren et al. (2017) The Granulocyte Progenitor Stage Is a Key Target of IRF8-Mediated Regulation of Myeloid-Derived Suppressor Cell Production. J Immunol 198:4129-4139
Mayor, Paul C; Eng, Kevin H; Singel, Kelly L et al. (2017) Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. J Allergy Clin Immunol :
Singh, Anurag K; Winslow, Timothy B; Kermany, Mohammad Habiby et al. (2017) A Pilot Study of Stereotactic Body Radiation Therapy Combined with Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma. Clin Cancer Res 23:5055-5065
Abrams, Scott I; Netherby, Colleen S; Twum, Danielle Y F et al. (2016) Relevance of Interferon Regulatory Factor-8 Expression in Myeloid-Tumor Interactions. J Interferon Cytokine Res 36:442-53
Eng, Jason W-L; Mace, Thomas A; Sharma, Rohit et al. (2016) Pancreatic cancer stem cells in patient pancreatic xenografts are sensitive to drozitumab, an agonistic antibody against DR5. J Immunother Cancer 4:33

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