Abstract 903: Mechanisms mediating hypoxic memory of type I IFN signaling suppression and implications for immune evasion in luminal breast cancer cells
Authors: Rebecca Marker, Aidan Moriarty, Remi Klotz, Min Yu
Journal: Cancer Research (2025)

Abstract Solid tumors often contain patches of hypoxic regions that yield aggressive, pro-metastatic phenotypes. Prevention and understanding of metastases is critical for the future of breast cancer research, as metastatic cancer is extremely difficult to manage and treat. Recent work in our lab has shown that long-term hypoxia suppresses type I interferon (IFN) signaling in breast cancer cells. Even upon reoxygenation, these gene expression changes are maintained, indicative of “hypoxic memory.” Breast cancer cells that have disseminated from the primary tumor as circulating tumor cells with this “post-hypoxic” memory phenotype show enhanced metastatic potential. IFNs typically boost and enhance immune cell activity through interferon-stimulated genes (ISGs); thus, hypoxic suppression of IFN signaling yields an immunosuppressive tumor microenvironment. 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-suppressive properties, and correlated with presence of tumor-infiltrating lymphocytes 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 a hypoxic memory. To try to understand possible mechanisms of hypoxic suppression, we overexpressed interferon regulatory factors (IRFs), which are positive regulators of the type I IFN pathway. However, this did not rescue hypoxic suppression and memory of IFI44L, suggesting that IRFs are not the sole regulator of IFN and ISG expression in hypoxia. Additional experiments are currently ongoing in the lab to address other possible mechanisms of hypoxic suppression and memory of IFN signaling. Additionally, co-culture experiments of breast cancer cells with knockdown or overexpression of IFI44L with different immune cell populations will shed light on the role of IFI44L in immune interactions in the tumor and in circulation. 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 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 American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 903.