Abstract 1788: Converting radiation-mediated tumor control to tumor cure by manipulating the macrophage response to dying cells
Authors: Crittenden Marka R. , Baird Jason R. , Savage Talicia , Cottam Benjamin , Friedman David , Young Kristina , Newell Pippa , Nguyen Cynthia , Jackson Andrew M. , Gough Michael J. 
Published: August 2015

Abstract
High-dose radiation has the ability to produce large-scale cancer cell death at the tumor site over a short time frame with the potential to provide both antigen and the immunological adjuvants required for effective adaptive immune responses. However, both clinical and preclinical evidence suggests that in the absence of additional immune intervention, adaptive immune responses to distant tumors following radiation therapy are rare and ineffective.
In vitro and in vivo, dying cells are efficiently immunosuppressive. Mer is a member of a subgroup of receptor tyrosine kinases and its dominant ligand is Gas6, a protein S-related gene that has been shown to bind exposed phosphatidylserine (PS) on apoptotic cells. The Mer-Gas6-PS interaction results in phagocytosis of the apoptotic cell, and mice with inactivated Mer are defective in their handling of apoptotic cells. We hypothesized that Mer expression on tumor macrophages acted as a receptor for cancer cells killed by radiation therapy and resulted in differentiation of these macrophages into suppressive phenotypes. We demonstrate here that blocking the Mer interaction with irradiated cancer cells blocks suppressive differentiation of tumor macrophages, and Mer blockade combined with TGFβ blockade restored classical proinflammatory macrophage function in the presence of irradiated cancer cells. We demonstrate that Mer ligation results in accumulation of NFkB p50 in macrophages that is required for the switch from anti-inflammatory to pro-inflammatory cytokine secretion, but does not change or interfere with classical polarization as measured by arginase and iNOS expression. Using CT-guided radiation to treat tumors in immune competent wild-type or Mer-/- mice, we demonstrate that loss of Mer is not sufficient to change tumor growth and response to radiation therapy, but when combined with TGFβ blockade using an orally bioavailable small molecule results in significantly extended survival and tumor cures. This does not occur in the absence of radiation therapy, demonstrating that radiation-induced cell death is a necessary trigger for tumor cure in mice lacking Mer and TGFβ signaling. These data demonstrate that targeting specific suppressive pathways involved in the response to dying cells permits tumor clearance by cytotoxic therapy.
Citation Format: Marka R. Crittenden, Jason R. Baird, Talicia Savage, Benjamin Cottam, David Friedman, Kristina Young, Pippa Newell, Cynthia Nguyen, Andrew M. Jackson, Michael J. Gough. Converting radiation-mediated tumor control to tumor cure by manipulating the macrophage response to dying cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1788. doi:10.1158/1538-7445.AM2015-1788