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 #
5P01CA095426-13
Application #
8730544
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
Freud, Aharon G; Mundy-Bosse, Bethany L; Yu, Jianhua et al. (2017) The Broad Spectrum of Human Natural Killer Cell Diversity. Immunity 47:820-833
Duggan, Megan C; Stiff, Andrew R; Bainazar, Maryam et al. (2017) Identification of NRAS isoform 2 overexpression as a mechanism facilitating BRAF inhibitor resistance in malignant melanoma. Proc Natl Acad Sci U S A 114:9629-9634
Long, Meixiao; Beckwith, Kyle; Do, Priscilla et al. (2017) Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest 127:3052-3064
Victor, Aaron R; Nalin, Ansel P; Dong, Wenjuan et al. (2017) IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-?B. J Immunol 199:2333-2342
Wesolowski, Robert; Duggan, Megan C; Stiff, Andrew et al. (2017) Circulating myeloid-derived suppressor cells increase in patients undergoing neo-adjuvant chemotherapy for breast cancer. Cancer Immunol Immunother 66:1437-1447
Markowitz, Joseph; Wang, Jiang; Vangundy, Zach et al. (2017) Nitric oxide mediated inhibition of antigen presentation from DCs to CD4+ T cells in cancer and measurement of STAT1 nitration. Sci Rep 7:15424
Campbell, Amanda R; Duggan, Megan C; Suarez-Kelly, Lorena P et al. (2017) MICA-Expressing Monocytes Enhance Natural Killer Cell Fc Receptor-Mediated Antitumor Functions. Cancer Immunol Res 5:778-789
Suarez-Kelly, Lorena P; Campbell, Amanda R; Rampersaud, Isaac V et al. (2017) Fluorescent nanodiamonds engage innate immune effector cells: A potential vehicle for targeted anti-tumor immunotherapy. Nanomedicine 13:909-920
Dai, Hong-Sheng; Griffin, Nathaniel; Bolyard, Chelsea et al. (2017) The Fc Domain of Immunoglobulin Is Sufficient to Bridge NK Cells with Virally Infected Cells. Immunity 47:159-170.e10
McMichael, Elizabeth L; Jaime-Ramirez, Alena Cristina; Guenterberg, Kristan D et al. (2017) IL-21 Enhances Natural Killer Cell Response to Cetuximab-Coated Pancreatic Tumor Cells. Clin Cancer Res 23:489-502

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