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Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade

Oncogene volume 38, pages 390–405 (2019)Cite this article

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Abstract

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.

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Acknowledgements

This work is supported by US Army Breast Cancer Research Program (W81XWH-14-1-0237 to YH; W81XWH-14-1-0238 to NED/SO), Breast Cancer Research Foundation (to NED and SO), NIH/NCI P30CA047904 and Natural Science Foundation of China (81502366 to YQ).

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Authors and Affiliations

  1. Women’s Cancer Research Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Ye Qin, Shauna N. Vasilatos, Lin Chen, Hao Wu, Steffi Oesterreich & Yi Huang

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ye Qin, Min Huang, Steffi Oesterreich & Yi Huang

  3. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Zhishen Cao & Anda M. Vlad

  4. Allegheny General Hospital Pathology, Pittsburgh, PA, USA

    Yumei Fu

  5. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Anda M. Vlad & Binfeng Lu

  6. Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, and University of Washington, Seattle, WA, USA

    Nancy E. Davidson

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  1. Ye Qin
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Qin, Y., Vasilatos, S.N., Chen, L. et al. Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade. Oncogene 38, 390–405 (2019). https://doi.org/10.1038/s41388-018-0451-5

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