Rejection of metastatic 4T1 breast cancer by attenuation of Treg cells in combination with immune stimulation
Rejection of metastatic 4T1 breast cancer by attenuation of Treg cells in combination with immune stimulation
复制标题
DOI：
10.1038/sj.mt.6300310
复制
发表时间：
2007-12-01
影响因子：
12.4
通讯作者：
Woo, Savio L. C.
中科院分区：
文献类型：
--
作者：
Chen, Li;Huang, Tian-Gui;Woo, Savio L. C.
4 T1乳腺癌是一种高度恶性和免疫原性差的鼠肿瘤模型，类似于人类晚期乳腺癌，并且对大多数基于免疫刺激的治疗是难治的。我们假设免疫刺激治疗的无效性是由CD 4（+）CD 25（+）调节性T（Treg）细胞的抑制作用介导的，这可以通过将糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白与其天然配体（GITRL）结合来减弱;此外，与现有免疫刺激方案的联合治疗将增强抗肿瘤免疫力并根除小鼠中的转移性4 T1肿瘤。在分子水平上构建了小鼠GITRL的可溶性同二聚体形式（mIg-mGITRL），并用于治疗在免疫活性的同基因Balb/c小鼠中建立的原位4 T1肿瘤。当与腺病毒介导的瘤内鼠粒细胞巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-12（IL-12）基因递送加上全身性4-1BB激活联合应用时，mIg-mGITRL减弱了脾Treg细胞的免疫抑制功能，这导致干扰素-γ（IFN-γ）水平升高。（IFN-γ）的产生，肿瘤特异性溶细胞T细胞活性，肿瘤排斥反应和长期生存的65%的动物没有明显的毒性。结果表明，将mIg-mGITRL添加到免疫刺激治疗方案中显著改善了长期生存，而没有明显的毒性，并且可能在临床上转化为患者转移性乳腺癌的有效和安全的治疗方式。
4T1 breast carcinoma is a highly malignant and poorly immunogenic murine tumor model that resembles advanced breast cancer in humans, and is refractory to most immune stimulation-based treatments. We hypothesize that the ineffectiveness of immune stimulatory treatment is mediated by the suppressive effects of CD4(+)CD25(+) regulatory T (Treg) cells, which can be attenuated by engaging the glucocorticoid-induced tumor necrosis factor receptor family-related protein with its natural ligand (GITRL); further, combination treatment with existing immune stimulation regimens will augment anti-tumor immunity and eradicate metastatic 4T1 tumors in mice. A soluble homodimeric form of mouse GITRL (mIg-mGITRLs) was molecularly constructed and used to treat orthotopic 4T1 tumors established in immune-competent, syngeneic Balb/c mice. When applied in combination with adenovirus-mediated intratumoral murine granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-12 (IL-12) gene delivery plus systemic 4-1BB activation, mIg-mGITRLs attenuated the immune-suppressive function of splenic Treg cells, which led to elevated interferon-gamma (IFN-gamma) production, tumor-specific cytolytic T-cell activities, tumor rejection and long-term survival in 65% of the animals without apparent toxicities. The results demonstrate that addition of mIg-mGITRLs to an immune-stimulatory treatment regimen significantly improved long-term survival without apparent toxicity, and could potentially be clinically translated into an effective and safe treatment modality for metastatic breast cancer in patients.