Abstract
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.
Highlights
Metastasis accounts for the majority of cancer-related deaths
We found that cryo-thermal-induced macrophage polarization toward the M1 phenotype was exclusively responsible for subsequent dendritic cells (DCs) maturation, differentiation of CD4+ T cells to Th1 and cytotoxic T cells (CTLs), and generation of cytotoxic CD8+ T cells, which in turn was crucial for mediating cryo-thermal-induced long-term anti-tumor memory
In this study, we revealed that cryo-thermal therapy remodeled the immune environment, triggering durable anti-tumor immune memory to inhibit metastasis in a B16F10 melanoma model
Summary
Metastasis accounts for the majority of cancer-related deaths. Conventional tumor therapy such as chemotherapy and radiotherapy alone can partially cure patients with advanced cancer, but their effectiveness for distant metastasis is limited[1]. Immunotherapy holds great promise for cancer treatment, stimulation of an immune response to completely prevent distant metastasis is still far from being satisfactory. Cancer cells exploit multiple mechanisms to create an immunosuppressive environment[2,3,4,5,6]. The therapeutic effect of immunotherapy can be greatly impaired by an immunosuppressive environment[1,7,8]. Reversing immunosuppression and inducing durable anti-tumor immunity are essential in cancer therapy
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