The membrane type matrix metalloproteinase MMP14 mediates constitutive shedding of MHC class I chain-related molecule A independent of A disintegrin and metalloproteinases.
The membrane type matrix metalloproteinase MMP14 mediates constitutive shedding of MHC class I chain-related molecule A independent of A disintegrin and metalloproteinases.
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DOI：
10.4049/jimmunol.0903789
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发表时间：
2010-04-01
期刊：
影响因子：
--
通讯作者：
Wu JD
中科院分区：
文献类型：
--
作者：
Liu G;Atteridge CL;Wang X;Lundgren AD;Wu JD
肿瘤细胞表面MHC I链相关分子A（云母）与NKG 2D的结合刺激NK和T细胞抗肿瘤免疫。肿瘤细胞释放云母有助于肿瘤免疫逃避，这可能部分促进肿瘤进展。因此，阐明肿瘤释放MIC的机制对于增强NK和T细胞抗肿瘤免疫的治疗具有重要意义。在此，我们报告了膜型基质金属蛋白酶（MT-MMP）MMP 14介导的云母脱落。MMP 14表达的抑制阻断云母脱落。伴随地，MMP 14的过表达增强云母脱落。MMP 14对云母脱落的调节不依赖于已报道介导云母脱落的亚当斯的活性。最后，MICA阳性肿瘤细胞中的MMP 14表达调节肿瘤细胞对NK细胞杀伤的敏感性。提示MMP 14可能成为肿瘤免疫治疗的新靶点。
Engagement of tumor cell surface MHC I chain related molecule A (MICA) to NKG2D stimulates NK and T cell anti-tumor immunity. Shedding of MICA by tumor cells facilitates tumor immune evasion, which may in part contribute to tumor progression. Thus, elucidating the mechanisms by which tumors shed MIC is of great importance for therapy to reinforce NK and T cell anti-tumor immunity. Herein we report that the membrane type matrix metalloproteinase (MT-MMP) MMP14 mediates MICA shedding. Suppression of MMP14 expression blocks MICA shedding. Concomitantly, overexpression of MMP14 enhances MICA shedding. The regulation of MICA shedding by MMP14 is independent of the activity of ADAMs which have been reported to mediate MICA shedding. Finally, MMP14 expression in MICA-positive tumor cells regulates the sensitivity of tumor cells to NK cell killing. These findings suggest that MMP14 may be a new target for tumor immune therapy.
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