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 (FcyRllla). 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 FcyR-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).

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
United States
Zip Code
Mani, R; Mao, Y; Frissora, F W et al. (2015) Tumor antigen ROR1 targeted drug delivery mediated selective leukemic but not normal B-cell cytotoxicity in chronic lymphocytic leukemia. Leukemia 29:346-55
Stephens, D M; Ruppert, A S; Jones, J A et al. (2014) Impact of targeted therapy on outcome of chronic lymphocytic leukemia patients with relapsed del(17p13.1) karyotype at a single center. Leukemia 28:1365-8
Trikha, Prashant; Carson 3rd, William E (2014) Signaling pathways involved in MDSC regulation. Biochim Biophys Acta 1846:55-65
Riches, John C; Gribben, John G (2014) Immunomodulation and immune reconstitution in chronic lymphocytic leukemia. Semin Hematol 51:228-34
Beckwith, K A; Frissora, F W; Stefanovski, M R et al. (2014) The CD37-targeted antibody-drug conjugate IMGN529 is highly active against human CLL and in a novel CD37 transgenic murine leukemia model. Leukemia 28:1501-10
Wu, Salene M; Yang, Hae-Chung; Thayer, Julian F et al. (2014) Association of the physiological stress response with depressive symptoms in patients with breast cancer. Psychosom Med 76:252-6
Dubovsky, Jason A; Flynn, Ryan; Du, Jing et al. (2014) Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 124:4867-76
Mishra, Anjali; Sullivan, Laura; Caligiuri, Michael A (2014) Molecular pathways: interleukin-15 signaling in health and in cancer. Clin Cancer Res 20:2044-50
Kohrt, Holbrook E; Sagiv-Barfi, Idit; Rafiq, Sarwish et al. (2014) Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 123:1957-60
Jones, Jeffrey A; Byrd, John C (2014) How will B-cell-receptor-targeted therapies change future CLL therapy? Blood 123:1455-60

Showing the most recent 10 out of 186 publications