Journal article
Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade
Oncogene, Vol.38(3), pp.390-405
01/2019
DOI: 10.1038/s41388-018-0451-5
PMCID: PMC6336685
PMID: 30111819
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.
Details
- Title: Subtitle
- Inhibition of histone lysine-specific demethylase 1 elicits breast tumor immunity and enhances antitumor efficacy of immune checkpoint blockade
- Creators
- Ye Qin - UPMC Hillman Cancer CenterShauna N Vasilatos - UPMC Hillman Cancer CenterLin Chen - UPMC Hillman Cancer CenterHao Wu - UPMC Hillman Cancer CenterZhishen Cao - University of PittsburghYumei Fu - Allegheny General HospitalMin Huang - University of PittsburghAnda M Vlad - University of PittsburghBinfeng Lu - University of PittsburghSteffi Oesterreich - UPMC Hillman Cancer CenterNancy E Davidson - Seattle Cancer Care AllianceYi Huang - UPMC Hillman Cancer Center
- Resource Type
- Journal article
- Publication Details
- Oncogene, Vol.38(3), pp.390-405
- DOI
- 10.1038/s41388-018-0451-5
- PMID
- 30111819
- PMCID
- PMC6336685
- ISSN
- 0950-9232
- eISSN
- 1476-5594
- Grant note
- P30 CA047904 / NCI NIH HHS W81XWH-14-1-0237 / DOD | Congressionally Directed Medical Research Programs (CDMRP) W81XWH-14-1-0238 / DOD | Congressionally Directed Medical Research Programs (CDMRP)
- Language
- English
- Date published
- 01/2019
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984383301302771
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