Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer.
Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer.
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DOI：
10.1158/0008-5472.can-16-1456
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发表时间：
2016-12-15
期刊：
影响因子：
11.2
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Metelli A;Wu BX;Fugle CW;Rachidi S;Sun S;Zhang Y;Wu J;Tomlinson S;Howe PH;Yang Y;Garrett-Mayer E;Liu B;Li Z
由Lrrc32基因编码的GARP是潜伏TGF-β的细胞表面对接受体，由血小板和调节性T细胞自然表达。虽然Lrrc32在乳腺癌中频繁扩增，但GARP在癌症中的表达及其相关功能尚未被探索。本文报道GARP发挥致癌作用，通过富集和激活肿瘤微环境中潜伏的TGF-β来促进免疫耐受。我们发现人类乳腺癌、肺癌和结肠癌中GARP表达异常。在正常乳腺上皮细胞和癌细胞的遗传学研究中，GARP表达增加TGF-β的生物活性，促进免疫缺陷小鼠的恶性转化。在具有免疫能力的乳腺癌小鼠中，GARP过表达促进了Foxp3+调节性T细胞活性，从而促进了癌症的进展和转移。值得注意的是，一组garp特异性单克隆抗体的施用限制了人乳腺癌原位模型的转移。总的来说，这些结果确定了GARP-TGF-β轴在肿瘤微环境中的致癌作用，并提出了可能用于诊断和治疗目的的机制。
GARP encoded by the Lrrc32 gene is the cell surface docking receptor for latent TGF-β which is expressed naturally by platelets and regulatory T cells. Although Lrrc32 is amplified frequently in breast cancer, the expression and relevant functions of GARP in cancer have not been explored. Here we report that GARP exerts oncogenic effects, promoting immune tolerance by enriching and activating latent TGF-β in the tumor microenvironment. We found that human breast, lung and colon cancers expressed GARP aberrantly. In genetic studies in normal mammary gland epithelial and carcinoma cells, GARP expression increased TGF-β bioactivity and promoted malignant transformation in immune deficient mice. In breast carcinoma-bearing mice that were immune competent, GARP overexpression promoted Foxp3+ regulatory T cell activity, which in turn contributed to enhancing cancer progression and metastasis. Notably, administration of a panel of GARP-specific monoclonal antibodies limited metastasis in an orthotopic model of human breast cancer. Overall, these results define the oncogenic effects of the GARP-TGF-β axis in the tumor microenvironment and suggest mechanisms that might be exploited for diagnostic and therapeutic purposes.