Immunotherapy strategies have been emerging as powerful weapons against cancer. Early clinical trials reveal that overall response to immunotherapy is low in breast cancer patients, suggesting that effective strategies to overcome resistance to immunotherapy are urgently needed. In this study, we investigated whether epigenetic reprograming by modulating histone methylation could enhance effector T lymphocyte trafficking and improve therapeutic efficacy of immune checkpoint blockade in breast cancer with focus on triple-negative breast cancer (TNBC) subtype. In silico analysis of The Cancer Genome Atlas (TCGA) data shows that expression of histone lysine-specific demethylase 1 (LSD1) is inversely associated with the levels of cytotoxic T cell-attracting chemokines (C-C motif chemokine ligand 5 (CCL5), C-X-C motif chemokine ligand 9 and 10 (CXCL9, CXCL10)) and programmed death-ligand 1 (PD-L1) in clinical TNBC specimens. Tiling chromatin immunoprecipitation study showed that re-expression of chemokines by LSD1 inhibition is associated with increased H3K4me2 levels at proximal promoter regions. Rescue experiments using concurrent treatment with small interfering RNA or inhibitor of chemokine receptors blocked LSD1 inhibitor-enhanced CD8+ T cell migration, indicating a critical role of key T cell chemokines in LSD1-mediated CD8+ lymphocyte trafficking to the tumor microenvironment. In mice bearing TNBC xenograft tumors, anti-PD-1 antibody alone failed to elicit obvious therapeutic effect. However, combining LSD1 inhibitors with PD-1 antibody significantly suppressed tumor growth and pulmonary metastasis, which was associated with reduced Ki-67 level and augmented CD8+ T cell infiltration in xenograft tumors. Overall, these results suggest that LSD1 inhibition may be an effective adjuvant treatment with immunotherapy as a novel management strategy for poorly immunogenic breast tumors.

中文翻译：

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组蛋白赖氨酸特异性去甲基化酶 1 的抑制可引发乳腺肿瘤免疫并增强免疫检查点阻断的抗肿瘤功效。

免疫治疗策略已成为对抗癌症的强大武器。早期临床试验表明，乳腺癌患者对免疫治疗的总体反应较低，这表明迫切需要克服免疫治疗耐药性的有效策略。在本研究中，我们研究了通过调节组蛋白甲基化进行表观遗传重编程是否可以增强效应 T 淋巴细胞运输并提高乳腺癌免疫检查点阻断的治疗效果，重点关注三阴性乳腺癌 (TNBC) 亚型。癌症基因组图谱 (TCGA) 数据的计算机分析表明，组蛋白赖氨酸特异性脱甲基酶 1 (LSD1) 的表达与细胞毒性 T 细胞吸引趋化因子（CC 基序趋化因子配体 5 (CCL5)、CXC 基序）的水平呈负相关。临床 TNBC 标本中的趋化因子配体 9 和 10（CXCL9、CXCL10））和程序性死亡配体 1（PD-L1）。平铺染色质免疫沉淀研究表明，LSD1 抑制导致的趋化因子重新表达与近端启动子区域 H3K4me2 水平升高相关。使用小干扰 RNA 或趋化因子受体抑制剂同时治疗的拯救实验阻断了 LSD1 抑制剂增强的 CD8+ T 细胞迁移，表明关键 T 细胞趋化因子在 LSD1 介导的 CD8+ 淋巴细胞向肿瘤微环境的运输中发挥着关键作用。在携带 TNBC 异种移植肿瘤的小鼠中，单独使用抗 PD-1 抗体未能产生明显的治疗效果。然而，LSD1 抑制剂与 PD-1 抗体相结合可显着抑制肿瘤生长和肺转移，这与异种移植肿瘤中 Ki-67 水平降低和 CD8+ T 细胞浸润增加有关。总的来说，这些结果表明 LSD1 抑制可能是免疫疗法的有效辅助治疗，作为免疫原性差的乳腺肿瘤的一种新的治疗策略。