Multiple negative regulatory mechanisms exist that act to dampen the immune response to immune-based treatments. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. Their numbers correlate with tumor burden and are predictive of overall survival. MDSC have been shown to reside in the peripheral blood, lymphoid tissue, and tumor tissue of mice in a number of experimental models. MDSC can inhibit the proliferation and cytotoxic activity of T cells in tumor-bearing animals through multiple mechanisms, and studies in murine models indicate that disruption of MDSC function can reverse immune tolerance to tumor antigens, stimulate anti-tumor immune responses, and induce tumor regressions. We have investigated the inhibitory effects of MDSC on human immune cells and found that they inhibit cytokine signal transduction within innate immune effector cells. Our murine experiments demonstrate that the abundant MDSC in tumor-bearing mice produce large amounts of nitric oxide which leads to increased nitration of tyrosine residues on signal transduction proteins and impaired responsiveness of immune effector cells to stimulatory signals. Also, we have recently been able to show that MDSC markedly inhibit the ability of natural killer (NK) cells to lyse monoclonal antibody (mAb)-coated tumor cells via effects on signal transduction downstream of the receptor for the constant (or """"""""Fc"""""""") region of immunoglobulin G (Fc?Rllla). We now propose to explore the effects of MDSC on the response of the innate immune system to mAb-coated tumor cells and devise methods to reverse their inhibitory actions for application to the immunotherapy of cancer. We hypothesize that MDSC inhibit the innate immune response to therapeutic mAbs via the release of nitric oxide and that depletion or deactivation of this cell population will augment the activity of mAb-based therapies.
In Aim 1, we plan to characterize the inhibitory effects of MDSC on the Fc?R-dependent effector functions of NK cells and monocytes in vitro In Aim 2, we will test methods for the depletion/deactivation of MDSC in murine models in preparation for phase I trials in humans where anti-MDSC treatments will be combined with mAb therapy (Aim 3)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA095426-13
Application #
8730546
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
DUNS #
City
Columbus
State
OH
Country
United States
Zip Code
43210
Victor, Aaron R; Weigel, Christoph; Scoville, Steven D et al. (2018) Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development. J Immunol 200:565-572
Byrd, John C; Ruppert, Amy S; Heerema, Nyla A et al. (2018) Lenalidomide consolidation benefits patients with CLL receiving chemoimmunotherapy: results for CALGB 10404 (Alliance). Blood Adv 2:1705-1718
Scoville, Steven D; Nalin, Ansel P; Chen, Luxi et al. (2018) Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function. Blood 132:1792-1804
Latchana, Nicholas; DiVincenzo, Mallory J; Regan, Kelly et al. (2018) Alterations in patient plasma microRNA expression profiles following resection of metastatic melanoma. J Surg Oncol 118:501-509
Chan, Wing Keung; Kang, Siwen; Youssef, Youssef et al. (2018) A CS1-NKG2D Bispecific Antibody Collectively Activates Cytolytic Immune Cells against Multiple Myeloma. Cancer Immunol Res 6:776-787
Lai, Xiulan; Stiff, Andrew; Duggan, Megan et al. (2018) Modeling combination therapy for breast cancer with BET and immune checkpoint inhibitors. Proc Natl Acad Sci U S A 115:5534-5539
Dai, Hong-Sheng; Caligiuri, Michael A (2018) Molecular Basis for the Recognition of Herpes Simplex Virus Type 1 Infection by Human Natural Killer Cells. Front Immunol 9:183
Byrd, John C; Smith, Stephen; Wagner-Johnston, Nina et al. (2018) First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. Oncotarget 9:13023-13035
Chen, Luxi; Youssef, Youssef; Robinson, Cameron et al. (2018) CD56 Expression Marks Human Group 2 Innate Lymphoid Cell Divergence from a Shared NK Cell and Group 3 Innate Lymphoid Cell Developmental Pathway. Immunity 49:464-476.e4
Olaverria Salavaggione, Gonzalo N; Duggan, Megan C; Carson, William E (2018) Analysis of MLN4924 (pevonedistat) as a potential therapeutic agent in malignant melanoma. Melanoma Res 28:390-397

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