Resistance to cytotoxic T cells is frequently mediated by loss of MHC class I expression or IFNγ signaling in tumor cells, such as mutations of B2M or JAK1 genes. Natural killer (NK) cells could potentially target such resistant tumors, but suitable NK-cell–based strategies remain to be developed. We hypothesized that such tumors could be targeted by NK cells if sufficient activating signals were provided. Human tumors frequently express the MICA and MICB ligands of the activating NKG2D receptor, but proteolytic shedding of MICA/B represents an important immune evasion mechanism in many human cancers. We showed that B2M - and JAK1 -deficient metastases were targeted by NK cells following treatment with a mAb that blocks MICA/B shedding. We also demonstrated that the FDA-approved HDAC inhibitor panobinostat and a MICA/B antibody acted synergistically to enhance MICA/B surface expression on tumor cells. The HDAC inhibitor enhanced MICA/B gene expression, whereas the MICA/B antibody stabilized the synthesized protein on the cell surface. The combination of panobinostat and the MICA/B antibody reduced the number of pulmonary metastases formed by a human melanoma cell line in NOD/SCID gamma mice reconstituted with human NK cells. NK-cell–mediated immunity induced by a mAb specific for MICA/B, therefore, provides an opportunity to target tumors with mutations that render them resistant to cytotoxic T cells.

中文翻译：

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MICA和MICB脱落的抑制作用引发NK细胞介导的抗细胞毒性T细胞肿瘤的免疫力。

对细胞毒性T细胞的抗性通常是由肿瘤细胞中MHC I类表达或IFNγ信号传导的丧失（例如B2M或JAK1基因的突变）介导的。天然杀伤（NK）细胞可能潜在地靶向这种抗药性肿瘤，但是基于NK细胞的合适策略仍有待开发。我们假设如果提供足够的激活信号，NK细胞就可以靶向此类肿瘤。人类肿瘤经常表达激活的NKG2D受体的MICA和MICB配体，但是MICA / B的蛋白水解脱落代表了许多人类癌症中重要的免疫逃逸机制。我们显示，在用阻断MICA / B脱落的mAb处理后，NK细胞靶向B2M和JAK1缺陷转移。我们还证明了FDA批准的HDAC抑制剂panobinostat和MICA / B抗体具有协同作用，可增强肿瘤细胞上MICA / B的表面表达。HDAC抑制剂增强了MICA / B基因的表达，而MICA / B抗体稳定了细胞表面合成的蛋白质。panobinostat和MICA / B抗体的组合减少了由人NK细胞重构的NOD / SCIDγ小鼠中由人黑素瘤细胞系形成的肺转移的数量。因此，由MICA / B特异的mAb诱导的NK细胞介导的免疫力提供了靶向具有突变的肿瘤的机会，这些突变使它们对细胞毒性T细胞具有抗性。而MICA / B抗体则将合成的蛋白质稳定在细胞表面。panobinostat和MICA / B抗体的组合减少了由人NK细胞重构的NOD / SCIDγ小鼠中由人黑素瘤细胞系形成的肺转移的数量。因此，由MICA / B特异的mAb诱导的NK细胞介导的免疫力提供了靶向具有突变的肿瘤的机会，这些突变使它们对细胞毒性T细胞具有抗性。而MICA / B抗体则将合成的蛋白质稳定在细胞表面。panobinostat和MICA / B抗体的组合减少了由人NK细胞重构的NOD / SCIDγ小鼠中由人黑素瘤细胞系形成的肺转移的数量。因此，由MICA / B特异的mAb诱导的NK细胞介导的免疫力提供了靶向具有突变的肿瘤的机会，这些突变使它们对细胞毒性T细胞具有抗性。