Abstract 2840: Efficacy of Radiation Therapy in Mammary Carcinomas is Regulated by Macrophages

Abstract In patients with locally advanced breast cancer, radiation therapy (RT) and chemotherapy following surgery has been a mainstay of treatment with demonstrated survival advantage in numerous randomized trials. However, despite recent advances in treatment, many women still ultimately succumb to disease highlighting the need to improve therapeutic strategies. Results from several groups have recently revealed that the therapeutic effects of RT are in part dependent on activation of immune-mediated mechanism(s); however, little is known regarding the mechanistic details of this activation. To address this, we examined changes in the immune microenvironment of mammary carcinomas following RT. We found that following RT (5 Gy), the density of infiltrating macrophages was significantly increased (20 vs 35%, p = 0.02) as compared to mammary tumors in mice not receiving RT. When macrophages were depleted following RT, via use of a CSF-1 antagonist, a significant delay in tumor growth, as compared to tumors treated with RT alone was observed. Since this data indicated that macrophage infiltration blunted RT responsiveness, we hypothesized that reprogramming tumor-infiltrating macrophages more towards a classical cytotoxic phenotype would result in enhanced RT response and delayed tumor re-growth. Thus, we treated tumor-bearing mice with anti-IL-4 neutralizing mABs in combination with RT, and evaluated tumor re-growth, as compared to tumor-bearing mice treated with either RT or anti-IL4 mAB alone, and found that indeed, reprogramming tumor-infiltrating macrophages to favor classical (M1)-type activity significantly enhanced RT response and delayed tumor re-growth. Together these studies indicate that: 1) RT induces macrophage infiltration into mammary tumors, 2) protumor-type macrophages infiltrating mammary carcinomas blunt response to RT, and 3) reprogramming of tumor-infiltrating macrophages to favor a cytotoxic phenotype improves efficacy of RT. This work was supported by grants from the NIH/NCI, and Era of Hope (W81XWH-06-1-0416), and Program in Mesothelioma (PR080717) grants from the Department of Defense to LMC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2840. doi:10.1158/1538-7445.AM2011-2840