Many cancer therapies are being developed for the induction of durable anti-tumor immunity, especially for malignant tumors. The activation of antigen-presenting cells (APCs), including macrophages and dendritic cells (DCs), can bridge innate and adaptive immune responses against tumors. However, APCs have an immunosuppressive phenotype and reversing it for effective tumor-specific antigen presenting is critical in developing new cancer treatment strategies. We previously developed a novel cryo-thermal therapy to treat malignant melanoma in a mouse model; long-term survival and durable anti-tumor immunity were achieved, but the mechanism involved was unclear. This study revealed cryo-thermal therapy-induced macrophage polarization to the M1 phenotype and modulated the phenotypic and functional maturation of DCs with high expression of co-stimulatory molecules, increased pro-inflammatory cytokine production, and downregulated immuno-inhibitory molecule expression. Further, we observed CD4 + T-cell differentiation into Th1 and cytotoxic T-cell sub-lineages and generation of cytotoxic CD8 + T cells, in which M1 macrophage polarization had a direct, important role. The results indicated that cryo-thermal-induced macrophage polarization to the M1 phenotype was essential to mediate durable anti-tumor immunity, leading to long-term survival. Thus, cryo-thermal therapy is a promising strategy to reshape host immunosuppression, trigger persistent memory immunity for tumor eradication, and inhibit metastasis in the long term.

He & Lisa X. Xu (2019) Cryo-thermal therapy inducing MI macrophage polarization created CXCL10 and IL-6-rich pro-inflammatory environment for CD4 + T cell-mediated anti-tumor immunity,

Previous, we established a novel therapeutic approach to tumour of cryo-thermal therapy, which can induce durable anti-tumour memory immunity mediated by CD4+ T cell, and contribute to prolonged survival in B16F10 murine melanoma model and 4T1 murine mammary carcinoma. It has become apparent that innate immune cells are involved in the regulation of adaptive T cell immunity. Our previous studies revealed that cryo-thermal therapy induced M1 macrophage polarization and DCs maturation were required for the shaping of systemic long-lived T cell mediated anti-tumour memory immunity. Eosinophils are multifunctional innate effector cells and there is lack of knowledge on the role of eosinophils in cryo-thermal-induced anti-tumour immunity. This study revealed that cryo-thermal therapy activated eosinophils in spleen at early stage following the treatment. Furthermore, cryo-thermal-activated eosinophils exerted versatile immunologic regulation from innate immunity to anti-tumour adaptive immunity, such as M1 macrophage polarization, DCs maturation, differentiation of CD4-CTL subtypes and enhanced cytotoxicity of CD8+ T cells. Our study indicated that the cryo-thermal-activated eosinophils was essential for the shaping of durable anti-tumour memory immunity. Thus, our results present a new concept for eosinophils mediated anti-tumour immunity after cryo-thermal therapy.

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.