Calnexin Impairs the Antitumor Immunity of CD4+ and CD8+ T Cells
Calnexin Impairs the Antitumor Immunity of CD4+ and CD8+ T Cells
复制标题
钙联蛋白损害 CD4( ) 和 CD8( ) T 细胞的抗肿瘤免疫
DOI：
10.1158/2326-6066.cir-18-0124
复制
发表时间：
2019-01-01
影响因子：
10.1
通讯作者：
Wang, Zhi
中科院分区：
文献类型：
--
作者：
Chen, Yichen;Ma, Da;Wang, Zhi
阐明t细胞介导的抗肿瘤反应机制将为肿瘤免疫疗法的合理设计和发展提供信息。本研究发现，一种内质网（ER）伴侣蛋白calnexin在口腔鳞状细胞癌（OSCC）中显著上调。其在OSCC细胞上的膜性表达上调与肿瘤组织中t细胞浸润受到抑制有关，并与OSCC患者生存不良相关。我们发现calnexin抑制从健康供者和OSCC患者全血中分离的CD4（+）和CD8(+) T细胞的增殖，并抑制这些细胞的IFN γ、TNF α和IL2的分泌。此外，在黑色素瘤模型中，敲低calnexin可增强T细胞在肿瘤微环境中的浸润和效应功能，从而更好地控制肿瘤生长，而重组calnexin蛋白则会损害T细胞的浸润和效应功能，促进肿瘤生长。我们还发现calnexin通过抑制PD-1启动子中CpG岛的DNA甲基化状态，增强了PD-1在CD4（+）和CD8(+) T细胞上的表达。因此，这项工作揭示了肿瘤细胞中calnexin调节t细胞抗肿瘤反应的机制，并提示calnexin可能作为改善抗肿瘤免疫治疗的潜在靶点。
Elucidation of the mechanisms of T-cellmediated antitumor responses will provide information for the rational design and development of cancer immunotherapies. Here, we found that calnexin, an endoplasmic reticulum (ER) chaperone protein, is significantly upregulated in oral squamous cell carcinoma (OSCC). Upregulation of its membranous expression on OSCC cells is associated with inhibited T-cell infiltration in tumor tissues and correlates with poor survival of patients with OSCC. We found that calnexin inhibits the proliferation of CD4(+) and CD8(+) T cells isolated from the whole blood of healthy donors and patients with OSCC and inhibits the secretion of IFN gamma, TNF alpha, and IL2 from these cells. Furthermore, in a melanoma model, knockdown of calnexin enhanced the infiltration and effector functions of T cells in the tumor microenvironment and conferred better control of tumor growth, whereas treatment with a recombinant calnexin protein impaired the infiltration and effector functions of T cells and promoted tumor growth. We also found that calnexin enhanced the expression of PD-1 on CD4(+) and CD8(+) T cells by restraining the DNA methylation status of a CpG island in the PD-1 promoter. Thus, this work uncovers a mechanism by which T-cell antitumor responses are regulated by calnexin in tumor cells and suggests that calnexin might serve as a potential target for the improvement of antitumor immunotherapy.