实验性乳腺癌模型中 Foxp3 的治疗性阻断。
Therapeutic blockade of Foxp3 in experimental breast cancer models.
机构信息
Instituto de Investigaciones Biomédicas (INBIOMED), Facultad de Medicina, CONICET, Universidad de Buenos Aires, Paraguay 2155, piso 10, Buenos Aires, C1121ABG, Argentina.
Departamento de Biología Celular e Histología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
出版信息
Breast Cancer Res Treat. 2017 Nov;166(2):393-405. doi: 10.1007/s10549-017-4414-2. Epub 2017 Jul 29.
PURPOSE
Regulatory T cells (Tregs) impair the clinical benefit of cancer immunotherapy. To optimize the antitumor efficacy of therapeutic dendritic cell (DC) vaccines, we aimed to inhibit Foxp3, a transcription factor required for Treg function.
METHODS
Mice bearing established syngeneic LM3 and 4T1 breast tumors were treated with antitumor DC vaccines and a synthetic peptide (P60) that has been shown to inhibit Foxp3.
RESULTS
Treatment with P60 improved the therapeutic efficacy of DC vaccines in these experimental models. In addition, monotherapy with P60 inhibited tumor growth in immunocompetent as well as in immuno-compromised animals bearing established tumors. We found expression of Foxp3 in human and murine breast tumor cells. P60 inhibited IL-10 secretion in breast cancer cells that expressed Foxp3.
CONCLUSIONS
Our results suggest that Foxp3 blockade improves the therapeutic efficacy of DC vaccines by inhibition of Tregs and through a direct antitumor effect. This strategy could prove useful to neutralize the immunosuppressive microenvironment and to boost antitumor immunity in breast cancer.
目的
调节性 T 细胞（Tregs）削弱了癌症免疫疗法的临床获益。为了优化治疗性树突状细胞（DC）疫苗的抗肿瘤疗效，我们旨在抑制 Foxp3，这是 Treg 功能所必需的转录因子。
方法
用抗肿瘤 DC 疫苗和已证明可抑制 Foxp3 的合成肽（P60）治疗携带已建立的同源 LM3 和 4T1 乳腺癌肿瘤的小鼠。
结果
P60 处理改善了这些实验模型中 DC 疫苗的治疗效果。此外，P60 单药治疗可抑制免疫功能正常和携带已建立肿瘤的免疫功能低下动物的肿瘤生长。我们在人类和鼠乳腺癌细胞中发现了 Foxp3 的表达。P60 抑制了表达 Foxp3 的乳腺癌细胞中 IL-10 的分泌。
结论
我们的结果表明，Foxp3 阻断通过抑制 Tregs 并通过直接抗肿瘤作用来提高 DC 疫苗的治疗效果。该策略可能有助于中和免疫抑制微环境并增强乳腺癌中的抗肿瘤免疫。
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