Our long term goal is to understand the regulation of monocyte/macrophage Fey receptor (FcyR) function and to apply this knowledge to enhance the efficacy of monoclonal antibody therapy for cancer. Macrophages are critical effector cells in antibody therapy, and their strength of response is governed by the ratio of activating to inhibiting FcyR and by intracellular phosphatases such as SHIP. We recently uncovered some additional and unexpected features of both FcyR and SHIP that significantly impact the responses of these cells to antibody-coated targets. Firstly, we discovered that the activating FcyRI and FcyRlla not only mediate different functions but are also subject to differential regulation by SHIP, with FcyRlla being more strongly suppressed. Secondly, we identified the GDP dissociation inhibitor LyGDI as a binding partner of SHIP and a regulator of FcyR function. Both SHIP and LyGDI are likely relevant clinically, as we found a significant upregulation of both in CLL patient monocytes compared to healthy age-matched controls. Importantly, because SHIP associates more strongly with FcyRlla than with FcyRI, upregulation of these molecules may prevent therapeutic antibodies, especially those engineered for stronger FcyRlla binding, from reaching their full functional potential. In efforts to reverse this suppressed phenotype, we discovered that certain Toll-like receptor (TLR) and Nodlike receptor (NLR) agonists could enhance FcyR function, thus providing potential therapeutic opportunities. In order to bridge the gap between these findings and improved treatment modalities, we need to fully elucidate the mechanism(s) behind this tumor-associated FcyR regulation and to test in depth the effects of these TLR/NLR agonists on monocyte/macrophage FcyR function. Thus, here we propose to test our hypothesis that monocyte / macrophage FcyR function is critically regulated by SHIP and its effector LyGDI, and that TLR and NLR agonists have the potential to reverse this regulation, thus permitting a more effective response during antibody therapy. In completing these studies we will have elucidated the mechanism of LyGDI effect on FcyR function tested promising methods of enhancing FcyR function both in vitro and in vivo, and examined the mechanism whereby tumor cells suppress monocyte FcyR function. We strongly believe that by pursuing these basic biological findings we will uncover clinically relevant ways to both overcome this immunosuppression and to optimize antibody-based treatments.

Public Health Relevance

Although antibody therapy is a powerful treatment modality for a wide range of tumor types, the high expression of inhibitory proteins, SHIP and LyGDI, in monocytes works against this therapy. The function of FcyR, the immune receptors mediating antibody therapy, is thus significantly suppressed in cancer patients. Here, we propose to examine these negative regulatory mechanisms in depth and test whether certain bacterial ligands can reverse this suppression to enhance antibody-mediated tumor clearance.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA095426-11
Application #
8291536
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (J1))
Project Start
2002-02-01
Project End
2017-08-31
Budget Start
2012-09-19
Budget End
2013-08-31
Support Year
11
Fiscal Year
2012
Total Cost
$335,152
Indirect Cost
$101,237
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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

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