Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy.
Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy.
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DOI：
10.4049/jimmunol.1800885
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发表时间：
2018-11-01
期刊：
影响因子：
--
通讯作者：
Barouch DH
中科院分区：
文献类型：
--
作者：
Badamchi-Zadeh A;Moynihan KD;Larocca RA;Aid M;Provine NM;Iampietro MJ;Kinnear E;Penaloza-MacMaster P;Abbink P;Blass E;Tregoning JS;Irvine DJ;Barouch DH
组蛋白脱乙酰酶（HDAC）和溴和额外末端（BET）家族的蛋白质的组合抑制最近在鼠研究中显示出针对黑素瘤、胰腺导管腺癌、睾丸和淋巴瘤癌症的治疗功效。然而，在这些研究中，免疫系统在治疗控制这些癌症中的作用尚未被探索。我们试图研究HDAC抑制剂romidepsin（RMD）和BET抑制剂IBET 151单独和组合对疫苗引发的免疫应答的影响。在用RMD、IBET 151或RMD+ IBET 151处理下，在初免-加强方案中用不同的疫苗系统（腺病毒、蛋白质）免疫C57 BL/6小鼠。在疫苗接种期间RMD+ IBET 151的组合施用导致抗原特异性CD 8 T细胞的频率和数量显著增加。RMD+ IBET 151处理显著增加疫苗引发的IFN-γ+脾CD 8 T细胞的频率，并赋予针对B16-OVA黑色素瘤的上级的治疗性和预防性保护。RNA-Seq分析显示，RMD+ IBET 151和未处理的抗原特异性CD 8 T细胞之间具有很强的转录相似性，除了细胞凋亡和IL-6信号相关基因的差异表达。在RMD+ IBET 151处理后，血清IL-6在体内显著增加，其中重组IL-6施用复制了RMD+ IBET 151处理对疫苗引发的CD 8 T细胞应答的作用。未评估IL-6保护的充分性。组合的HDAC和BET抑制导致更大的疫苗引发的CD 8 T细胞应答和增强的针对B16-OVA黑色素瘤的治疗性和预防性保护。RMD+ IBET 151治疗后IL-6产生增加以及促凋亡基因和抗凋亡基因的差异表达可能有助于增强癌症疫苗应答。
The combined inhibition of histone deacetylases (HDAC) and the proteins of the bromo and extra terminal (BET) family have recently shown therapeutic efficacy against melanoma, pancreatic ductal adenocarcinoma, testicular and lymphoma cancers in murine studies. However, in such studies the role of the immune system in therapeutically controlling these cancers has not been explored. We sought to investigate the effect of the HDAC inhibitor romidepsi n (RMD) and the BET inhibitor IBET151, both singly and in combination, on vaccine elicited immune responses. C57BL/6 mice were immunized with differing vaccine systems (adenoviral, protein) in prime-boost regimens, under treatment with RMD, IBET151, or RMD+IBET151. The combined administration of RMD+IBET151 during vaccination resulted in a significant increase in the frequency and number of antigen-specific CD8 T cells. RMD+IBET151 treatment significantly increased the frequency of vaccine-elicited IFN-γ+ splenic CD8 T cells and conferred superior therapeutic and prophylactic protection against B16-OVA melanoma. RNA-Seq analyses revealed strong transcriptional similarity between RMD+IBET151 and untreated antigen-specific CD8 T cells, except in apoptosis and IL-6 signaling-related genes that were differentially expressed. Serum IL-6 was significantly increased in vivo following RMD+IBET151 treatment, with recombinant IL-6 administration replicating the effect of RMD+IBET151 treatment on vaccine-elicited CD8 T cell responses. IL-6 sufficiency for protection was not assessed. Combined HDAC and BET inhibition resulted in greater vaccine-elicited CD8 T cell responses and enhanced therapeutic and prophylactic protection against B16-OVA melanoma. Increased IL-6 production and the differential expression of pro- and anti-apoptotic genes following RMD+IBET151 treatment are likely contributors to the enhanced cancer vaccine responses.
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DOI：
10.1084/jem.20120994
发表时间：
2012-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ma CS;Deenick EK;Batten M;Tangye SG
通讯作者：
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影响因子：
5.3
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Jostes S;Nettersheim D;Fellermeyer M;Schneider S;Hafezi F;Honecker F;Schumacher V;Geyer M;Kristiansen G;Schorle H
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发表时间：
2014-09
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通讯作者：
Prinjha, Rab K.
影响因子：
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