{
  "abstract": "Background Epigenetic alterations can disrupt gene functions and lead to cellular neoplastic transformation and cancer progression. 1 Lysine-specific demethylase 1 (LSD1) overexpression is observed in various cancers, including triple-negative breast cancers (TNBC).2 Recent studies have also demonstrated that epigenetic modifiers influence transcriptome programs involved in carcinogenesis, as well as tumor cell-immunogenicity and immune cell dynamics.3 Considering limited subsets of patients respond to immunotherapies for TNBC subtypes, epigenetic-mediated mechanistic changes on TNBC pathogenicity is essential to uncover novel biomarkers and combination treatment strategies. In this study, in-vitro functional studies were performed to investigate the oncogenic role of LSD1 in TNBC and evaluated clinical potential of epigenetic modifying agents coupled immunotherapies through in-vivo studies.Methods We analysed approximately 300 TNBC cases diagnosed at Singapore General Hospital, subjected to immunohistochemistry, immuno-scoring, spatial transcriptomics and multiplex immuno-oncology proteomics profiling with LSD1 IHC status. Human breast cells (MCF10A, MDA-MB-231) were cultured for cell-based assays and multi-omics profiling (RNA-seq, ChIP-seq). Cell-derived xenograft (CDX)-humanized mice model transplanted with MDA-MB-231 cells, received intraperitoneal LSD1 inhibitors alone or combined with immunotherapy agents.Results LSD1-positive TNBC cases were significantly associated with worse survival outcomes, characterized by activated hypoxia-mediated pathways and dampened immune cell infiltration/immunogenicity. In contrast, LSD1-negative TNBC cases present significantly higher proportions of intratumoral T cells, B cells, NK cells, M1-like TAMs and PD-L1 levels. Functional assays demonstrated LSD1 inhibition significantly reduces breast cancer cell clonogenicity and proliferation, while increasing PD-L1 levels. To identify LSD1-bound regions that contribute to TNBC progression, ChIP-seq analysis revealed 3039 upregulated LSD1-bound regions enriched for hypoxia and angiogenesis-related gene signatures. Motif analysis revealed enriched sequence motifs for AP-1 complex, and co-immunoprecipitation assays confirmed LSD1 interaction with several AP-1 factors. Importantly, cell-derived xenograft humanized mice models treated with immunotherapy combinations (nivolumab, ipilimumab, cobolimab)-coupled LSD1 inhibitor significantly reduced tumor size compared to control group.Conclusions Our study underscores the clinical potential of LSD1-targeted epigenetic drugs to sensitize TNBC tumors to immunotherapies. Additionally, our findings suggest LSD1 cooperates with the AP-1 transcriptional complex to drive oncogenic gene expression programs that promote tumor progression and immune evasion in TNBC, defining a novel LSD1-AP-1 transcriptional axis in TNBC. These findings support combination strategies incorporating LSD1 inhibitors with immune checkpoint blockade for improved therapeutic outcomes in TNBC.References Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010 Jan;31(1):27–36. doi: 10.1093/carcin/bgp220. Epub 2009 Sep 13. PMID: 19752007; PMCID: PMC2802667.Hayami S, Kelly JD, Cho HS, Yoshimatsu M, Unoki M, Tsunoda T, Field HI, Neal DE, Yamaue H, Ponder BA, Nakamura Y, Hamamoto R. Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers. Int J Cancer. 2011 Feb 1;128(3):574-86. doi: 10.1002/ijc.25349. PMID: 20333681.Micevic G, Bosenberg MW, Yan Q. The crossroads of cancer epigenetics and immune checkpoint therapy. Clin Cancer Res. 2023 Apr 3;29(7):1173-1182. doi: 10.1158/1078-0432.CCR-22-0784. PMID: 36449280; PMCID: PMC10073242.Ethics Approval Ethics approval was obtained from The Centralized Institutional Review Board of Singhealth, Singapore.Consent Consent was waived for this study from The Centralized Institutional Review Board of Singhealth, Singapore.",
  "authors": [
    {
      "affiliations": [
        "Singapore General Hospital, Singapore, Singapore"
      ],
      "name": "Dong Yeul Lee"
    },
    {
      "affiliations": [
        "Duke-NUS Medical School, Singapore, Singapore"
      ],
      "name": "Jing Han Hong"
    },
    {
      "affiliations": [
        "Genome Institute of Singapore, Singapore, Singapore"
      ],
      "name": "Peiyong Guan"
    },
    {
      "affiliations": [
        "National Cancer Centre Singapore, Singapore, Singapore"
      ],
      "name": "Bin Tean Teh"
    },
    {
      "affiliations": [
        "Singapore General Hospital, Singapore, Singapore"
      ],
      "name": "Jabed Iqbal"
    }
  ],
  "title": "486 Lysine-specific demethylase 1 (LSD1) inhibition modulates tumor progression and immunotherapeutic priming effects in triple-negative breast cancers",
  "uid": "32bf93c7-6a24-5941-9137-e405c936a5af"
}