CCL5 Deficiency Enhanced Cryo–Thermal-Triggered Long-Term Anti-Tumor Immunity in 4T1 Murine Breast Cancer

Abstract

Breast cancer remains one of the most common solid tumors. Tumor immunosuppressive factors mainly hinder the control of tumors. We previously developed an innovative cryo–thermal therapy that was shown to significantly suppress distal metastasis and improve long-term survival in murine B16F10 melanoma and 4T1 mammary carcinoma models. However, the effect of cryo–thermal therapy on the 4T1 model was not excellent. CCL5 has been reported to help the progression of breast cancer, so in this study, CCL5−/− was used to explore the role of host-derived CCL5 after cryo–thermal therapy. CCL5−/− could not completely resist tumor development, but it significantly improved survival rates when combined with cryo–thermal therapy. Mechanically, CCL5−/− mildly decreases the percentage of MDSCs, increases DC maturation and macrophage’s inflammatory function at an early stage after tumor inoculation, and later up-regulate the level of Th1 and down-regulate the level of Tregs. When combined with cryo–thermal therapy, CCL5−/− dramatically down-regulated the proportion of MDSCs and induced full M1 macrophage polarization, which further promoted Th1 differentiation and the cytotoxicity of CD8+ T cells. Our results indicated that CCL5−/− contributed to cryo–thermal-triggered, long-lasting anti-tumor memory immunity. The combination of cryo–thermal therapy and CCL5 blockades might extend the survival rates of patients with aggressive breast cancer.

Keywords

• CCL5
• cryo–thermal therapy
• breast cancer
• anti-tumor immunity