Department of Pathology and Cancer Institute, New York University School of Medicine, New York, NY, USA.
EMBO Mol Med. 2013 Sep;5(9):1311-21. doi: 10.1002/emmm.201302989. Epub 2013 Aug 6.
Store-operated calcium entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels regulates the function of many immune cells. Patients with loss-of-function mutations in the CRAC channel genes ORAI1 or STIM1 are immunodeficient and are prone to develop virus-associated tumours. This and the reported role of Ca(2+) signals in cytotoxic lymphocyte function suggest that SOCE may be critical for tumour immune surveillance. Using conditional knock out mice lacking STIM1 and its homologue STIM2, we find that SOCE in CD8(+) T cells is required to prevent the engraftment of melanoma and colon carcinoma cells and to control tumour growth. SOCE is essential for the cytotoxic function of CTLs both in vivo and in vitro by regulating the degranulation of CTLs, their expression of Fas ligand and production of TNF-α and IFN-γ. Our results emphasize an important role of SOCE in antitumour immunity, which is significant given recent reports arguing in favour of CRAC channel inhibition for cancer therapy.
钙库操纵性钙内流（SOCE）通过钙释放激活钙（CRAC）通道调节许多免疫细胞的功能。CRAC 通道基因 ORAI1 或 STIM1 功能丧失突变的患者免疫功能低下，容易发生与病毒相关的肿瘤。这与钙信号在细胞毒性淋巴细胞功能中的作用有关，表明 SOCE 可能对肿瘤免疫监测至关重要。使用缺乏 STIM1 及其同源物 STIM2 的条件敲除小鼠，我们发现 CD8(+)T 细胞中的 SOCE 可防止黑色素瘤和结肠癌细胞的植入，并控制肿瘤生长。SOCE 通过调节 CTL 的脱颗粒、Fas 配体的表达以及 TNF-α 和 IFN-γ 的产生，在体内和体外均对 CTL 的细胞毒性功能至关重要。我们的研究结果强调了 SOCE 在抗肿瘤免疫中的重要作用，鉴于最近有报道支持抑制 CRAC 通道进行癌症治疗，这一结果意义重大。
