Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors.
Histone deacetylase (HDAC) inhibitor ACY241 enhances anti-tumor activities of antigen-specific central memory cytotoxic T lymphocytes against multiple myeloma and solid tumors.
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DOI：
10.1038/s41375-018-0062-8
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发表时间：
2018-09
期刊：
影响因子：
11.4
通讯作者：
Anderson KC
中科院分区：
文献类型：
--
作者：
Bae J;Hideshima T;Tai YT;Song Y;Richardson P;Raje N;Munshi NC;Anderson KC
组蛋白去乙酰化酶（HDAC）是多种癌症的治疗靶点。ACY 241是HDAC 6选择性抑制剂，与免疫调节药物和蛋白酶体抑制剂联合使用时显示出抗多发性骨髓瘤（MM）活性。我们发现ACY 241显著降低了CD 138 + MM细胞、CD 4 + CD 25 + FoxP 3+调节性T细胞和HLA-DR低/-CD 11b + CD 33+骨髓源性抑制细胞的频率;并降低了CD 8 + T细胞上PD 1/PD-L1的表达和骨髓瘤患者骨髓细胞中免疫检查点的表达。ACY 241增加肿瘤和树突状细胞上的B7（CD 80，CD 86）和MHC（I类，II类）表达。我们进一步评估了ACY 241对用异型性XBP 1未剪接184 -192（YISPWILAV）和XBP 1剪接367 -375（YLFPQLISV）肽产生的抗原特异性细胞毒性T淋巴细胞（CTL）的作用。ACY 241以剂量和时间依赖性方式诱导共刺激（CD 28、41 BB、CD 40 L、OX 40）和活化（CD 38）分子表达，并具有抗肿瘤活性，表现为穿孔素/CD 107 a表达、IFN-γ/IL-2/TNF-α产生和抗原特异性中枢记忆CTL增加。ACY 241对抗原特异性记忆T细胞的这些作用与下游AKT/mTOR/p65通路的激活和转录调节因子（包括Bcl-6、Eomes、HIF-1和T-bet）的上调有关。因此，这些研究证明了ACY 241增强免疫应答的机制，为其单独和联合使用以恢复宿主抗肿瘤免疫力和改善患者结局提供了理论基础。
Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+CD25+FoxP3+ regulatory T cells, and HLA-DRLow/-CD11b+CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients. ACY241 increased B7 (CD80, CD86) and MHC (Class I, Class II) expression on tumor and dendritic cells. We further evaluated the effect of ACY241 on antigen-specific cytotoxic T lymphocytes (CTL) generated with heteroclitic XBP1unspliced184–192 (YISPWILAV) and XBP1spliced367–375 (YLFPQLISV) peptides. ACY241 induces co-stimulatory (CD28, 41BB, CD40L, OX40) and activation (CD38) molecule expression in a dose- and time-dependent manner, and anti-tumor activities, evidenced by increased perforin/CD107a expression, IFN-γ/IL-2/TNF-α production, and antigen-specific central memory CTL. These effects of ACY241 on antigen-specific memory T cells were associated with activation of downstream AKT/mTOR/p65 pathways and upregulation of transcription regulators including Bcl-6, Eomes, HIF-1 and T-bet. These studies therefore demonstrate mechanisms whereby ACY241 augments immune response, providing the rationale for its use, alone and in combination, to restore host anti-tumor immunity and improve patient outcome.
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