Abstract A28: Impact of macrophage function on the efficacy of radiation therapy

Abstract

Abstract In patients with locally advanced breast cancer, radiation therapy (RT) and chemotherapy following surgery has been a mainstay of treatment for breast cancer with demonstrated survival advantage in numerous randomized trials. However, despite recent advances in treatment, many women still ultimately succumb to this disease highlighting the need to improve our therapeutic options. Previous work from other groups demonstrated that the therapeutic effects of RT depend in part on activation of the immune system, but little is known about the details of this activation. To address this, we explored the effects of RT on the immune microenvironment in a syngeneic orthotopic murine transplantation model of breast cancer and found that 7 days following RT tumors had significantly increased numbers of CD11b+ macrophages compared to untreated tumors. When we depleted these macrophages using a CSF1 inhibitor or CSF1 blocking Ab following RT we found significantly delayed tumor growth compared to RT alone. Tumor-associated macrophages (TAMs) are key orchestrators of the tumor microenvironment and can be either classically-activated expressing cytotoxic molecules leading to tumor cell death (“anti-tumor”) or alternatively-activated in which they secrete proangiogenic, prosurvival, and proinvasive factors that foster tumor progression (“pro-tumor”). Given the delayed growth when TAMs were depleted following RT, we hypothesized that the infiltrating TAMs are predominantly of the pro-tumor phenotype and that a milieu that favors an anti-tumor phenotype would enhance the effect of RT. We tested this hypothesis using a blocking antibody against IL-4, the predominant cytokine which drives the alternatively-activated phenotype, and we observed significantly reduced tumor growth in mice treated with the combination of RT and IL-4 blockade compared to mice treated with either agent alone. These studies indicate that infiltrating macrophages following RT have a protumor function, and that conversion of these macrophages to a cytotoxic phenotype may improve the efficacy of RT. Citation Format: Stephen L. Shiao, David G. DeNardo, Bruce A. Faddegon, David M. Underhill, Catherine C. Park, Lisa M. Coussens. Impact of macrophage function on the efficacy of radiation therapy. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A28. doi:10.1158/1538-7445.CHTME14-A28