Abstract P027: MUC1-C integrates chronic activation of the type I and II interferon pathways in treatment resistance of triple-negative breast cancer

Abstract

Abstract Chronic inflammation is intimately linked to cancer progression and resistance to treatment. Triple-negative breast cancer (TNBC) is a recalcitrant malignancy largely unresponsive to cytotoxic, targeted and immunotherapeutic agents. The MUC1-C transmembrane protein, which is aberrantly expressed in TNBCs, evolved in mammals to provide protection of epithelia from the external environment. MUC1-C is activated in epithelial cell responses to inflammation and damage, and induces inflammatory, proliferative and remodeling signaling pathways that are associated with wound healing. However, prolonged MUC1-C activation in settings of chronic inflammation promotes cancer progression and treatment resistance. Recent studies in TNBCs have demonstrated that MUC1-C drives intrinsic activation of type II interferon (IFN) pathway that is linked to chronic inflammation and immune evasion (Yamashita N, et al. JITC 2021). In extending this work, we have now found that MUC1-C activates the type I IFN pathway, which contributes to genomic instability and DNA damage tolerance in TNBC cells. Importantly, our results further demonstrate that MUC1-C interacts with interferon regulatory factor 1 (IRF1) as a key regulatory node in integrating activation of the type I and II IFN pathways. We show that stimulation of TNBC cells with IFN-γ induces nuclear complexes of MUC1-C and IRF1 that drive expression of effectors, such as IDO1 and WARS, which promote immunosuppression in the tumor microenvironment (TME). Of translational relevance, analysis of human TNBC bulk and single cell RNA-seq datasets demonstrated that MUC1 associates with (i) IDO1 and WARS expression, and (ii) depletion and dysfunction of CD8+ T cells in the TNBC TME. Our results further demonstrate that MUC1-C and IRF1 complexes are necessary for induction of RIG-I, MDA5 and STING expression and for IFN-β production in TNBC cells. Consistent with these findings, we show that MUC1-C is necessary for activation of the downstream type I IFN pathway and IFN-related DNA damage resistance gene signature, which includes ISG15, a ubiquitin-like protein that links chronic inflammation and DNA damage resistance. Of translational relevance, studies in BRCA wild type and mutant TNBC cells treated with carboplatin or the PARP inhibitor olaparib demonstrate that MUC1-C is necessary for expression of RIG-I, MDA5, cGAS, STING and ISG15 and that targeting MUC1-C abrogates this response. As a result, MUC1-C is a target for inhibiting DNA damage tolerance and synergistically sensitizing TNBC cells to platinum-based agents and olaparib. In summary, these findings in TNBC uncover an essential role for MUC1-C and IRF1 in chronic activation of the type I and II IFN pathways that promote immune evasion and resistance to replicative stress. Our findings also support MUC1-C as a target for TNBC treatment with chimeric antigen receptor T cells, antibody-drug conjugates and a functional inhibitor that are under preclinical and clinical development. Citation Format: Nami Yamashita, Atsushi Fushimi, Yoshihiro Morimoto, Atrayee Bhattacharya, Mark Long, Song Liu, Donald Kufe. MUC1-C integrates chronic activation of the type I and II interferon pathways in treatment resistance of triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P027.