Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells
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DOI：
10.1038/s41598-019-42237-3
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发表时间：
2019-04-16
影响因子：
4.6
通讯作者：
Villagra, Alejandro
中科院分区：
文献类型：
--
作者：
Knox, Tessa;Sahakian, Eva;Villagra, Alejandro
组蛋白去乙酰化酶（HDAC）参与多种细胞调控机制，包括染色质环境外的非经典功能。一些出版物已经证明，选择性HDAC抑制剂（HDACi）可以影响肿瘤免疫原性和特异性免疫细胞的功能活性。特别地，已经报道HDAC 6的选择性抑制减少几种恶性肿瘤中的肿瘤生长。然而，仍然没有明确的细胞成分介导这种效果。在这项研究中，我们评估了HDAC 6 i Nexturastat A作为促发剂，以促进肿瘤微环境从“冷”到“热”的转变，并可能增强免疫检查点阻断疗法。这种组合方式被证明在同系黑色素瘤肿瘤模型中显著减少肿瘤生长。此外，我们观察到抗PD-1阻断治疗诱导的PD-L1和其他免疫抑制途径的上调完全中和。这种组合还显示了肿瘤微环境的深刻变化，例如免疫细胞浸润增强，中枢和效应T细胞记忆增加，以及促肿瘤发生M2巨噬细胞的显著减少。对肿瘤微环境的各个组分的评价表明，HDAC 6 i的体内抗肿瘤活性是通过其对肿瘤细胞和肿瘤相关巨噬细胞的作用介导的，而不是直接通过T细胞介导的。总体而言，我们的结果表明，选择性HDAC 6 i可用作免疫引发剂，以使免疫学上的“冷”肿瘤敏感，并随后改善正在进行的免疫检查点阻断疗法。
Histone deacetylases (HDACs) are involved in diverse cellular regulatory mechanisms including non-canonical functions outside the chromatin environment. Several publications have demonstrated that selective HDAC inhibitors (HDACi) can influence tumor immunogenicity and the functional activity of specific immune cells. In particular, the selective inhibition of HDAC6 has been reported to decrease tumor growth in several malignancies. However, there is still no clarity about the cellular components mediating this effect. In this study, we evaluated the HDAC6i Nexturastat A as a priming agent to facilitate the transition of the tumor microenvironment from "cold" to "hot", and potentially augment immune check-point blockade therapies. This combination modality demonstrated to significantly reduce tumor growth in syngeneic melanoma tumor models. Additionally, we observed a complete neutralization of the up-regulation of PD-L1 and other immunosuppressive pathways induced by the treatment with anti-PD-1 blockade. This combination also showed profound changes in the tumor microenvironment such as enhanced infiltration of immune cells, increased central and effector T cell memory, and a significant reduction of pro-tumorigenic M2 macrophages. The evaluation of individual components of the tumor microenvironment suggested that the in vivo anti-tumor activity of HDAC6i is mediated by its effect on tumor cells and tumor-associated macrophages, and not directly over T cells. Overall, our results indicate that selective HDAC6i could be used as immunological priming agents to sensitize immunologically "cold" tumors and subsequently improve ongoing immune check-point blockade therapies.