School of Biomedical Engineering and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Cell Death Dis. 2019 Mar 4;10(3):216. doi: 10.1038/s41419-019-1459-7.
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.
许多癌症疗法正在被开发用于诱导持久的抗肿瘤免疫，特别是针对恶性肿瘤。抗原提呈细胞（APCs）的激活，包括巨噬细胞和树突状细胞（DCs），可以桥接针对肿瘤的先天和适应性免疫反应。然而，APCs 具有免疫抑制表型，为了有效地呈递肿瘤特异性抗原，逆转这种表型至关重要，这是开发新的癌症治疗策略的关键。我们之前开发了一种新的冷冻-热疗方法来治疗小鼠模型中的恶性黑色素瘤；实现了长期生存和持久的抗肿瘤免疫，但涉及的机制尚不清楚。本研究揭示了冷冻-热疗诱导的巨噬细胞向 M1 表型极化，并调节了 DC 的表型和功能成熟，表现为共刺激分子表达增加、促炎细胞因子产生增加和免疫抑制分子表达下调。此外，我们观察到 CD4 T 细胞分化为 Th1 和细胞毒性 T 细胞亚群，并产生细胞毒性 CD8 T 细胞，其中 M1 巨噬细胞极化起着直接的重要作用。结果表明，冷冻-热诱导的巨噬细胞向 M1 表型极化对于介导持久的抗肿瘤免疫至关重要，从而导致长期生存。因此，冷冻-热疗是一种有前途的策略，可以重塑宿主免疫抑制，引发持久的记忆免疫以清除肿瘤，并抑制长期转移。
