The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells.
The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells.
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DOI：
10.1186/2051-1426-2-8
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发表时间：
2014
影响因子：
10.9
通讯作者：
Prins RM
中科院分区：
文献类型：
--
作者：
Lisiero DN;Soto H;Everson RG;Liau LM;Prins RM
组蛋白脱乙酰酶(HDAC)抑制剂是一类具有强大的抗肿瘤活性的药物，据报道能够上调MHC和共刺激分子的表达。我们假设表观遗传药理免疫调节可以通过过继T细胞疗法使肿瘤对免疫介导的细胞死亡敏感。在体内B16黑色素瘤模型和体内非肿瘤荷瘤模型中，PAN-HDAC抑制剂LBH589与gp100特异性T细胞免疫治疗相结合。观察肿瘤消退情况、肿瘤特异性T细胞功能和表型、血清细胞因子水平。在过继细胞转移治疗中加入LBH589显著降低了肿瘤负担，同时保持了全身促炎水平。此外，LBH589能够提高gp100特异性T细胞的存活率，并显著降低系统和肿瘤内的T调节细胞数量。即使在没有肿瘤的情况下，LBH589也能够增强肿瘤特异性T细胞的增殖、保留和多功能状态，表明其作用是T细胞特异性的。此外，LBH589诱导T细胞中IL-2受体(CD25)和共刺激分子OX-40的水平显著升高。这些结果表明，LBH589对过继转移的T细胞的免疫调节为提高效应性CD8T细胞的体内抗肿瘤效果提供了一种新的机制。
Histone deacetylase (HDAC) inhibitors are a class of agents that have potent antitumor activity with a reported ability to upregulate MHC and costimulatory molecule expression. We hypothesized that epigenetic pharmacological immunomodulation could sensitize tumors to immune mediated cell death with an adoptive T cell therapy. The pan-HDAC inhibitor, LBH589, was combined with gp100 specific T cell immunotherapy in an in vivo B16 melanoma model and in an in vivo non-tumor bearing model. Tumor regression, tumor specific T cell function and phenotype, and serum cytokine levels were evaluated. Addition of LBH589 to an adoptive cell transfer therapy significantly decreased tumor burden while sustaining systemic pro-inflammatory levels. Furthermore, LBH589 was able to enhance gp100 specific T cell survival and significantly decrease T regulatory cell populations systemically and intratumorally. Even in the absence of tumor, LBH589 was able to enhance the proliferation, retention, and polyfunctional status of tumor specific T cells, suggesting its effects were T cell specific. In addition, LBH589 induced significantly higher levels of the IL-2 receptor (CD25) and the co-stimulatory molecule OX-40 in T cells. These results demonstrate that immunomodulation of adoptively transferred T cells by LBH589 provides a novel mechanism to increase in vivo antitumor efficacy of effector CD8 T cells.