T_H2-polarized CD4⁺ T Cells and macrophages limit efficacy of radiotherapy

Radiotherapy and chemotherapy following surgery are mainstays of treatment for breast cancer. Although multiple studies have recently revealed the significance of immune cells as mediators of chemotherapy response in breast cancer, less is known regarding roles for leukocytes as mediating outcomes following radiotherapy. To address this question, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to radiotherapy could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor-bearing mice with either a neutralizing mAb to colony-stimulating factor-1 (CSF-1) or a small-molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following radiotherapy. Delayed tumor growth in this setting was associated with increased presence of CD8⁺ T cells and reduced presence of CD4⁺ T cells, the main source of the T_H2 cytokine IL4 in mammary tumors. Selective depletion of CD4⁺ T cells or neutralization of IL4 in combination with radiotherapy phenocopied results following macrophage depletion, whereas depletion of CD8⁺ T cells abrogated improved response to radiotherapy following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the chemotherapy paclitaxel, resulted in slowed primary mammary tumor growth by CD8⁺ T-cell-dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant T_H2-based programs driving protumorigenic and immune-suppressive pathways in mammary (breast) tumors to improve outcomes.