Coupling the immunomodulatory properties of the HDAC6 inhibitor ACY241 with Oxaliplatin promotes robust anti-tumor response in non-small cell lung cancer.
Coupling the immunomodulatory properties of the HDAC6 inhibitor ACY241 with Oxaliplatin promotes robust anti-tumor response in non-small cell lung cancer.
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DOI：
10.1080/2162402x.2022.2042065
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发表时间：
2022
期刊：
影响因子：
7.2
通讯作者：
Adeegbe D
中科院分区：
文献类型：
--
作者：
Bag A;Schultz A;Bhimani S;Stringfield O;Dominguez W;Mo Q;Cen L;Adeegbe D
虽然HDAC抑制剂在血液癌症中显示出前景，但它们在实体癌中的功效仍然有限。在本研究中，我们评估了HDAC6抑制剂Citarinostat（ACY 241）对肺肿瘤免疫区室的免疫调节特性及其与奥沙利铂联合治疗的潜力。作为单一药物，ACY 241治疗促进了肺腺癌荷瘤小鼠肿瘤中T细胞浸润、活化、增殖和效应功能的增加。此外，肿瘤相关的巨噬细胞表现出抑制性配体的表达下调，有利于增加MHC和共刺激分子，除了更高的CCL4表达，有利于增加肿瘤中的T细胞数量。ACY241处理后肿瘤相关T细胞和巨噬细胞的RNA测序显示了显著的基因组变化，这与T细胞活力的改善、抑制性分子特征的减少和巨噬细胞能力的增强一致，以改善T细胞引发。最后，将这些ACY241介导的作用与化疗药物奥沙利铂偶联，导致肺癌荷瘤小鼠和患者源性肿瘤中肿瘤相关T细胞效应子功能显著增强。总的来说，我们的研究强调了ACY 241广泛的免疫调节活性的分子基础，并支持其作为与合理选择的化疗药物联合用于NSCLC治疗干预的伴侣药物的适用性。
While HDAC inhibitors have shown promise in hematologic cancers, their efficacy remains limited in solid cancers. In the present study, we evaluated the immunomodulatory properties of the HDAC6 inhibitor, Citarinostat (ACY241) on lung tumor immune compartment and its therapeutic potential in combination with Oxaliplatin. As a single agent, ACY241 treatment promoted increased infiltration, activation, proliferation, and effector function of T cells in the tumors of lung adenocarcinoma-bearing mice. Furthermore, tumor-associated macrophages exhibited downregulated expression of inhibitory ligands in favor of increased MHC and co-stimulatory molecules in addition to higher expression of CCL4 that favored increased T cell numbers in the tumors. RNA-sequencing of tumor-associated T cells and macrophages after ACY241 treatment revealed significant genomic changes that is consistent with improved T cell viability, reduced inhibitory molecular signature, and enhancement of macrophage capacity for improved T cell priming. Finally, coupling these ACY241-mediated effects with the chemotherapy drug Oxaliplatin led to significantly enhanced tumor-associated T cell effector functionality in lung cancer-bearing mice and in patient-derived tumors. Collectively, our studies highlight the molecular underpinnings of the expansive immunomodulatory activity of ACY241 and supports its suitability as a partner agent in combination with rationally selected chemotherapy agents for therapeutic intervention in NSCLC.