PII-075 - DNA METHYLTRANSFERASE INHIBITOR SYNERGIZE WITH IMMUNE CHECK POINT INHIBITORS IN THE TREATMENT OF TRIPLE NEGATIVE BREAST CANCER

X. wang¹, H. Gao², j. yu², D. Liu², M. Wang², R. Weinshilboum², L. Wang²; ¹wang.xue2@mayo.edu, ²Mayo Clinic.

Background: Triple Negative Breast Cancer (TNBC) is the most aggressive subtype of breast cancer (BC). Lack of druggable biomarkers such as estrogen receptors limited the treatment options and efficacy for TNBC. We previous identified a subgroup of TNBC tumors with high expression of DNA methylation transferases (DNMTs), and these tumors were responded to DNMT inhibitor (DNMTi) treatment in patient derived xenograft (PDX) models. It is known that DNMTi treatment activates interferon-mediated immune response in various types of cancer. However, whether the DNMTi treatment may crosstalk with immunotherapies, such as PD-L1 immune checkpoint inhibitor (ICI) treatment, in TNBC remain unclear.

Methods: In this study, we are aiming to determine whether DNMTi could affect PD-L1 inhibitor immunotherapy in BC. Two TNBC cell lines (BT549 and MDA-MB-231) were treated with vehicle or two DNMTis (decitabine, 5-aza-4’-thio-2’-deoxycytidine), respectively. Transcription-wide differentially expressed genes after DNMTi treatments were identified by RNA-seq, followed with biological pathways enrichment. Furthermore, immune intact mice (FVB) were used to establish two BC mouse models by injection of mouse BC cell lines (E0771 or KPB25L). Those BC mice were treatment with vehicle control, single DNMTi, anti-mouse PD-L1 monoclonal antibody, and combination of one DNMTi and PD-L1 antibody. Tumor size was measured to evaluate the treatment efficacy.

Results: RNA-seq identified highly enriched upregulated immune-related pathways such as interferon (IFN) signaling pathway, consistent between the two TNBC cell lines and two DNMTi. Using syngeneic BC mouse models, after 4 weeks treatment, the tumor produced by E0771 cells was significantly smaller in PD-L1 antibody treatment group compare with the control, while the tumor produced by KPB25L cells was lightly smaller in PD-L1 antibody treatment group compare with the control. Moreover, DNMTi alone was able to slow the tumor growth produced by both cell lines, and the combination of DNMTi and anti-PD-L1 was superior to individual treatment, regardless of their sensitivity to ICIs.

Conclusion: Our data suggested that DNMTi enhanced the response of TNBC to ICIs, probably via activating IFN signaling pathways. This study supports the future study of the application of DNMTi and immunotherapy in the treatment of TNBC.