HDAC inhibitors enhance the immunotherapy response of melanoma cells.
HDAC inhibitors enhance the immunotherapy response of melanoma cells.
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DOI：
10.18632/oncotarget.17950
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发表时间：
2017-10-10
期刊：
影响因子：
--
通讯作者：
Dent P
中科院分区：
文献类型：
--
作者：
Booth L;Roberts JL;Poklepovic A;Kirkwood J;Dent P
我们关注泛组蛋白去乙酰化酶（HDAC）抑制剂AR 42和丙戊酸钠改变黑色素瘤细胞免疫原性的能力。用HDAC抑制剂处理黑色素瘤细胞迅速降低了多种HDAC蛋白的表达以及PD-L1、PD-L2和ODC的水平，并增加了MHCA的表达。以细胞特异性的方式，黑素瘤分离株将免疫原性蛋白HMGB 1释放到细胞外环境中。在卵巢和H&NSCC PDX分离株中以及在来自肺和肾的已建立的肿瘤细胞系中获得了非常相似的数据。HDAC 1、HDAC 3、HDAC 8和HDAC 10而非HDAC 6的敲低概括了HDAC抑制剂对免疫治疗生物标志物的作用。使用B16小鼠黑素瘤细胞，我们发现用AR 42或丙戊酸钠预处理增强了抗PD-1抗体和抗CTLA 4抗体的抗肿瘤功效。在B16模型中，AR 42和丙戊酸钠均增强了多激酶抑制剂帕唑帕尼的抗肿瘤疗效。在来自暴露于[HDAC抑制剂+抗PD-1]但不暴露于[HDAC抑制剂+抗CTLA 4]的动物的血浆中，CCL 2、CCL 5、CXCL 9和CXCL 2的水平增加。来自HDAC抑制剂加抗PD-1暴露的肿瘤的细胞因子数据与增加的活化T细胞、M1巨噬细胞、中性粒细胞和NK细胞浸润相关。总的来说，我们的数据支持将泛HDAC抑制剂与激酶抑制剂或检查点抑制剂抗体组合使用作为新型黑色素瘤治疗策略。
We focused on the ability of the pan-histone deacetylase (HDAC) inhibitors AR42 and sodium valproate to alter the immunogenicity of melanoma cells. Treatment of melanoma cells with HDAC inhibitors rapidly reduced the expression of multiple HDAC proteins as well as the levels of PD-L1, PD-L2 and ODC, and increased expression of MHCA. In a cell-specific fashion, melanoma isolates released the immunogenic protein HMGB1 into the extracellular environment. Very similar data were obtained in ovarian and H&NSCC PDX isolates, and in established tumor cell lines from the lung and kidney. Knock down of HDAC1, HDAC3, HDAC8 and HDAC10, but not HDAC6, recapitulated the effects of the HDAC inhibitors on the immunotherapy biomarkers. Using B16 mouse melanoma cells we discovered that pre-treatment with AR42 or sodium valproate enhanced the anti-tumor efficacy of an anti-PD-1 antibody and of an anti-CTLA4 antibody. In the B16 model, both AR42 and sodium valproate enhanced the anti-tumor efficacy of the multi-kinase inhibitor pazopanib. In plasma from animals exposed to [HDAC inhibitor + anti-PD-1], but not [HDAC inhibitor + anti-CTLA4], the levels of CCL2, CCL5, CXCL9 and CXCL2 were increased. The cytokine data from HDAC inhibitor plus anti-PD-1 exposed tumors correlated with increased activated T cell, M1 macrophage, neutrophil and NK cell infiltration. Collectively, our data support the use of pan-HDAC inhibitors in combination with kinase inhibitors or with checkpoint inhibitor antibodies as novel melanoma therapeutic strategies.
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影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
5.2
作者：
Mawatari T;Ninomiya I;Inokuchi M;Harada S;Hayashi H;Oyama K;Makino I;Nakagawara H;Miyashita T;Tajima H;Takamura H;Fushida S;Ohta T
通讯作者：
Ohta T
影响因子：
16
作者：
Duran A;Amanchy R;Linares JF;Joshi J;Abu-Baker S;Porollo A;Hansen M;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT
影响因子：
5.6
作者：
Roberts JL;Tavallai M;Nourbakhsh A;Fidanza A;Cruz-Luna T;Smith E;Siembida P;Plamondon P;Cycon KA;Doern CD;Booth L;Dent P
通讯作者：
Dent P
影响因子：
3.6
作者：
Tavallai, Seyedmehrad;Hamed, Hossein A.;Dent, Paul
通讯作者：
Dent, Paul