HDAC inhibition potentiates immunotherapy in triple negative breast cancer.
HDAC inhibition potentiates immunotherapy in triple negative breast cancer.
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DOI：
10.18632/oncotarget.23169
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发表时间：
2017-12-26
期刊：
影响因子：
--
通讯作者：
Munster PN
中科院分区：
文献类型：
--
作者：
Terranova-Barberio M;Thomas S;Ali N;Pawlowska N;Park J;Krings G;Rosenblum MD;Budillon A;Munster PN
三阴性乳腺癌（TNBC）代表了一种更具侵袭性和困难的乳腺癌亚型，其中对化疗有反应，但毒性显著，耐药性往往随之而来。免疫疗法在包括乳腺癌在内的各种癌症中显示出有希望的结果。在这里，我们研究了一种新的组合策略，其中组蛋白脱乙酰酶抑制剂（HDACi）与免疫检查点抑制剂一起应用，以改善TNBC中的免疫治疗反应。测试不同的表观遗传修饰剂，我们专注于HDACi作为免疫疗法的引发调节剂的机制。将肿瘤细胞与人外周血单个核细胞（PBMC）共培养，并进行流式细胞术免疫表型分析，以确定表观遗传引发在促进肿瘤抗原呈递和免疫细胞活化中的作用。我们发现HDACi在TNBC细胞中以时间依赖性方式上调PD-L1 mRNA和蛋白表达，但在激素应答细胞中不上调。针对TNBC，HDACi在体外与PBMC共培养时上调肿瘤细胞上的PD-L1和HLA-DR，并下调CD 4 + Foxp 3 + Treg。HDACi显著增强了三阴性4 T1乳腺癌小鼠模型中对PD-1/CTLA-4阻断的体内反应，这是目前唯一可用的与人TNBC功能相似的实验系统。这导致肿瘤生长显著减少和存活率增加，与肿瘤微环境中T细胞肿瘤浸润增加和CD 4 + Foxp 3 + T细胞减少相关。总的来说，我们的研究结果表明HDAC抑制与免疫检查点抑制剂组合的新作用，并确定了一种有前途的治疗策略，支持其对TNBC治疗的进一步临床评价。
Triple-negative breast cancer (TNBC) represents a more aggressive and difficult subtype of breast cancer where responses to chemotherapy occur, but toxicity is significant and resistance often follows. Immunotherapy has shown promising results in various types of cancer, including breast cancer. Here, we investigated a new combination strategy where histone deacetylase inhibitors (HDACi) are applied with immune checkpoint inhibitors to improve immunotherapy responses in TNBC. Testing different epigenetic modifiers, we focused on the mechanisms underlying HDACi as priming modulators of immunotherapy. Tumor cells were co-cultured with human peripheral blood mononuclear cells (PBMCs) and flow cytometric immunophenotyping was performed to define the role of epigenetic priming in promoting tumor antigen presentation and immune cell activation. We found that HDACi up-regulate PD-L1 mRNA and protein expression in a time-dependent manner in TNBC cells, but not in hormone responsive cells. Focusing on TNBC, HDACi up-regulated PD-L1 and HLA-DR on tumor cells when co-cultured with PBMCs and down-regulated CD4+ Foxp3+ Treg in vitro. HDACi significantly enhanced the in vivo response to PD-1/CTLA-4 blockade in the triple-negative 4T1 breast cancer mouse model, the only currently available experimental system with functional resemblance to human TNBC. This resulted in a significant decrease in tumor growth and increased survival, associated with increased T cell tumor infiltration and a reduction in CD4+ Foxp3+ T cells in the tumor microenvironment. Overall, our results suggest a novel role for HDAC inhibition in combination with immune checkpoint inhibitors and identify a promising therapeutic strategy, supporting its further clinical evaluation for TNBC treatment.
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影响因子：
32.4
作者：
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16.6
作者：
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Balko JM