Abstract A110: Inhibition of MerTK in tumor infiltrating leukocytes decreases tumor growth in a mouse model of breast cancer
Authors: Jacobsen Kristen M. , Cook Rebecca S. , DeRyckere Deborah , Stanford Jamie , Hunter Debra M. , Wang Xiaodong , Frye Stephen , Graham Douglas K. , Earp H. Shelton 
Published: May 2015

Abstract
Tumor-associated macrophages (TAMs) and other myeloid-derived cells that infiltrate solid tumors function to support tumor growth, angiogenesis, proliferation and metastasis. Increased numbers of TAMs have also been associated with poor prognosis in breast cancer. Previous studies have shown that targeting TAMs, either by depletion or re-programming, is an effective method for reducing solid tumor growth. The receptor tyrosine kinase, MerTK, is expressed on macrophages and is involved in suppressing proinflammatory cytokine production following efferocytosis. Using orthotopic and transgenic mouse models of breast cancer, we demonstrated that MerTK inhibition in the tumor microenvironment is sufficient to decrease primary tumor growth and metastasis and increase tumor-free survival. Lethally irradiated MMTV-PyVmT mice transplanted with MerTK-/- bone marrow had a 2-fold reduction in tumor mass and volume and altered IL-6 production by tumor infiltrating CD11b+ cells compared to wild-type bone marrow recipients. Compared to orthotopic tumor-bearing wild-type mice, orthotopic tumor-bearing MerTK-/- mice also had enhanced serum levels of proinflammatory cytokines IL-12 and IL-6 as well as reduced expression of wound-healing and immunosuppressive cytokines, including IL-10. The tumor-infiltrating CD8+ lymphocyte population was also increased in tumor-bearing MerTK-/- mice and tumor growth could be restored by antibody-mediated CD8+ T cell depletion in this orthotopic PyVmT model. To futher investigate the potential for MerTK inhibition in the tumor microenvironment as a viable therapeutic strategy, the therapeutic efficacy of a novel MerTK-selective small molecule tyrosine kinase inhibitor (TKI) was evaluated in an orthotopic MerTK-negative mammary gland tumor model. After 3 weeks of daily treatment, tumor growth was reduced two-fold in mice treated with the TKI compared to mice treated with vehicle. Taken together, these results indicate that MerTK inhibition in tumor-infiltrating leukocytes leads to increased acute inflammatory cytokine production and stimulates CD8+ lymphocyte-mediated immune responses, leading to reduced tumor burden. The data also implicate MerTK in the tumor microenvironment as a promising novel therapeutic target in solid tumors, such as breast cancer and support further development of translational agents targeting MerTK
Citation Format: Kristen M. Jacobsen, Rebecca S. Cook, Deborah DeRyckere, Jamie Stanford, Debra M. Hunter, Xiaodong Wang, Stephen Frye, Douglas K. Graham, H. Shelton Earp. Inhibition of MerTK in tumor infiltrating leukocytes decreases tumor growth in a mouse model of breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A110.