The cryo-thermal therapy eradicated melanoma in mice by eliciting CD4(+) T-cell-mediated antitumor memory immune response.
The cryo-thermal therapy eradicated melanoma in mice by eliciting CD4(+) T-cell-mediated antitumor memory immune response.
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DOI：
10.1038/cddis.2017.125
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发表时间：
2017-03-23
影响因子：
9
通讯作者：
Xu LX
中科院分区：
文献类型：
--
作者：
He K;Liu P;Xu LX
肿瘤转移是肿瘤治疗中的一个主要问题。在我们之前的研究中，提出了一种新的肿瘤治疗方式——低温热疗法，强调了其对抑制远端转移并在 4T1 小鼠乳腺癌模型中实现长期生存的作用。为了证明在其他侵袭性肿瘤模型中的治疗效果并进一步研究诱导长期生存的机制，在本研究中，使用自发转移性小鼠B16F10黑色素瘤模型。低温热疗法可诱导植入的黑色素瘤消退并延长长期存活率，同时抑制肺转移。它还促进了 CD4+ CD25− 常规 T 细胞的激活，同时降低了脾、肺和血液中 CD4+ CD25+ 调节性 T 细胞 (Treg) 和骨髓源性抑制细胞 (MDSC) 的百分比。此外，治疗90天后，低温热疗法增强了CD8+ T细胞的溶细胞功能，并诱导CD8+ T细胞分化为记忆干T细胞（TSCM），并诱导CD4+ T细胞分化为脾脏中的优势CD4-CTL、Th1和Tfh亚群。研究发现，良好的治疗效果主要依赖于CD4+T细胞提供持久的记忆性抗肿瘤免疫反应。同时，还观察到血清IFN-γ显着升高，为抗肿瘤免疫提供了理想的微环境。进一步的研究表明，在治疗后45或60天，接受治疗的小鼠对B16F10而非GL261肿瘤的再次攻击产生排斥，这意味着治疗诱导了强烈的全身性和黑色素瘤特异性记忆抗肿瘤免疫。因此，低温热疗法将被认为是一种预防肿瘤复发和转移的新治疗策略，在不久的将来具有潜在的临床应用前景。
Tumor metastasis is a major concern in tumor therapy. In our previous studies, a novel tumor therapeutic modality of the cryo-thermal therapy has been presented, highlighting its effect on the suppression of distal metastasis and leading to long-term survival in 4T1 murine mammary carcinoma model. To demonstrate the therapeutic efficacy in other aggressive tumor models and further investigate the mechanism of long-term survival induced, in this study, spontaneous metastatic murine B16F10 melanoma model was used. The cryo-thermal therapy induced regression of implanted melanoma and prolonged long-term survival while inhibiting lung metastasis. It also promoted the activation of CD4+ CD25− conventional T cells, while reduced the percentage of CD4+ CD25+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the spleen, lung and blood. Furthermore, the cryo-thermal therapy enhanced the cytolytic function of CD8+ T cells and induced differentiation of CD8+ T cells into memory stem T cell (TSCM), and differentiation of CD4+ T cells into dominant CD4-CTL, Th1 and Tfh subsets in the spleen for 90 days after the treatment. It was found that good therapeutic effect was mainly dependent on CD4+ T cells providing a durable memory antitumor immune response. At the same time, significant increase of serum IFN-γ was also observed to provide an ideal microenvironment of antitumor immunity. Further study showed that the rejection of re-challenge of B16F10 but not GL261 tumor in the treated mice in 45 or 60 days after the treatment, implied a strong systemic and melanoma-specific memory antitumor immunity induced by the treatment. Thus the cryo-thermal therapy would be considered as a new therapeutic strategy to prevent tumor recurrence and metastasis with potential clinical applications in the near future.