Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer.
Modulation of NKG2D-ligand cell surface expression enhances immune cell therapy of cancer.
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DOI：
10.1097/cji.0b013e31820e1b0d
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Thorne SH
中科院分区：
文献类型：
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作者：
Huang B;Sikorski R;Sampath P;Thorne SH
提出用于治疗癌症的多种免疫细胞疗法，包括自体细胞（巨噬细胞因子激活的杀伤细胞、细胞因子诱导的杀伤细胞）或细胞系（TALL-104、NK-92），依赖于识别恶性细胞上的NKG 2D配体进行靶向。这些配体，例如人类中的云母和MICB是应激反应配体，并且通常但不是在肿瘤内普遍表达。已经报道了几种肿瘤逃逸机制，包括配体下调和内化，或蛋白水解切割和其暴露部分的脱落（释放可溶性云母和MICB; sMICA，sMICB）。因此，针对肿瘤细胞表面表达水平和这些配体的脱落对患者进行预筛选的能力将防止对不能应答的患者进行不必要的治疗，而对患者进行靶向预治疗以增加表面表达和/或阻断脱落将增强这些疗法的后续有效性。在这里，我们报告sMICA和sMICB血清试验结合肿瘤测量可用于确定肿瘤脱落率，并选择组蛋白去乙酰化酶抑制剂组合治疗（在某些肿瘤中上调细胞表面云母/B）和金属蛋白酶抑制剂（在其他情况下阻断云母/B脱落）可以在免疫细胞治疗之前掺入以调节细胞表面云母/B水平，显著增强其有效性（单独使用或作为溶瘤病毒的载体媒介物）。最终，接受这种免疫细胞治疗的患者的预筛选可能用于基于肿瘤的NKG 2D配体状态的个性化癌症治疗方案。
A variety of immune cell therapies proposed for use in the treatment of cancer, including both autologus cells (Lymphokine Activated Killer, Cytokine Induced Killer) or cell lines (TALL-104, NK-92), rely on recognition of NKG2D ligands on malignant cells for targeting. These ligands, such as MICA and MICB in humans are stress response ligands and are commonly, but not ubiquitously expressed within tumors. Several tumor escape mechanisms have been reported, including ligand down regulation and internalization, or proteolytic cleavage and shedding of their exposed portions (releasing soluble MICA and MICB; sMICA, sMICB). Therefore, an ability to pre-screen patients for the level of tumor cell surface expression and shedding of these ligands would prevent needless treatment of patients that are unable to respond, while targeted pre-treatment of patients to increase surface expression and/ or block shedding would enhance the subsequent effectiveness of these therapies. Here we report that serum tests of sMICA and sMICB in conjunction with tumor measurements might be used to determine rates of shedding from a tumor and that treatment with a selected combination of histone deacetylase inhibitors (to upregulate cell surface MICA/B in some tumors), and metalloproteinase inhibitors (to block MICA/B shedding in others) can be incorporated to regulate cell surface MICA/B levels prior to immune cell therapy, significantly enhancing their effectiveness (either used alone or as carrier vehicles for oncolytic viruses). Ultimately pre-screening patients undergoing such immune cell therapies might be used to personalize cancer treatment regimens based on the NKG2D-ligand status of the tumor.