Abstract A062: Mechanisms mediating hypoxic memory of type I IFN signaling suppression and implications for immune evasion in luminal breast cancer cells
Authors: Marker Rebecca , Moriarty Aidan , Klotz Remi , Yu Min 
Published: February 2025

Abstract
Prevention of metastases is critical for the future of breast cancer research, as metastatic cancer is extremely difficult to manage and treat. Solid tumors often contain patches of hypoxic regions that yield aggressive, pro-metastatic phenotypes. Recent work in our lab has shown that long-term hypoxia suppresses type I interferon (IFN) signaling in breast cancer cells, and this suppression of IFN signaling is maintained even after reoxygenation, indicative of “hypoxic memory.” Breast cancer cells and circulating tumor cells (CTCs) that have exited hypoxia but maintain such hypoxic memory showed enhanced metastatic potential. In addition to tumor intrinsic effects, IFN suppression can dampen surrounding immune cell populations within the tumor microenvironment, primarily through interferon-stimulated genes (ISGs) which carry out immune functions through activation of various immune cell populations. More research is needed to understand how ISGs are downregulated in hypoxia and how those changes in gene expression contribute to immunosuppressive ability of hypoxic and post-hypoxic cells. Interferon-inducible 44-like (IFI44L) is an ISG that has been associated with tumor-infiltrating lymphocytes and enhanced metastasis in other cancers, but its role in breast cancer has not been studied. We found that IFI44L is significantly suppressed in breast cancer cells in hypoxia and maintained after reoxygenation as hypoxic memory. Overexpressing interferon regulatory factors (IRFs), which are positive regulators of the type I IFN pathway, did not rescue hypoxic suppression and memory of IFI44L, suggesting IRFs are not the sole regulator of IFN and ISG expression in hypoxia. Current experiments in the lab are ongoing to address the mechanisms responsible for hypoxic memory of IFI44L suppression. Additionally, co-culture studies of IFI44L knockdown and overexpression breast cancer cell lines with different immune populations will shed light on the role of hypoxic suppression of IFI44L in immune evasion. To better understand implications of maintained IFI44L suppression, we will also examine immune cell activity and metastatic potential using in vivo mouse studies. We expect to see less immune cell effect and enhanced metastasis with IFI44L knockdown and reversed phenotypes with overexpression of IFI44L. Understanding mechanisms of immune suppression and evasion mediated via IFI44L can lead to strategies for targeting hypoxia-mediated tumorigenesis and metastasis.
Citation Format: Rebecca Marker, Aidan Moriarty, Remi Klotz, Min Yu. Mechanisms mediating hypoxic memory of type I IFN signaling suppression and implications for immune evasion in luminal breast cancer cells [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A062.