PO.IM02.05 · 免疫学
缺氧介导的IFI44L抑制及其记忆及其与STING在乳腺癌转移和免疫逃逸中的相互作用
Hypoxia-mediated suppression and memory of IFI44L and its interaction with STING in breast cancer metastasis and immune evasion
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
实体瘤常含有缺氧区域的斑块，产生侵袭性、促转移的表型。转移的预防和理解对乳腺癌研究的未来至关重要，因为转移性癌症极难管理和治疗。我们实验室近期的工作表明，长期缺氧抑制乳腺癌细胞中的I型干扰素（IFN）信号。即使在复氧后，这些基因表达变化仍得以维持，提示存在"缺氧记忆"。作为循环肿瘤细胞从原发肿瘤播散、具有这种"缺氧后"记忆表型的乳腺癌细胞显示出增强的转移潜能。IFN通常通过干扰素刺激基因（ISG）来促进和增强免疫细胞活性；因此，缺氧对IFN信号的抑制产生免疫抑制性肿瘤微环境。需要更多研究来理解ISG在缺氧中如何被下调，以及这些基因表达变化如何促成缺氧和缺氧后细胞的免疫抑制能力。干扰素诱导44样蛋白（IFI44L）是一种ISG，在其他癌症中已与抑瘤特性相关联，并与肿瘤浸润淋巴细胞的存在相关，但其在乳腺癌中的作用尚未被研究。我们发现IFI44L在缺氧的乳腺癌细胞中显著受到抑制，并在复氧后作为一种缺氧记忆得以维持。为理解缺氧记忆和IFI44L抑制的意义，我们在MCF7和NT2.5乳腺细胞系以及循环肿瘤细胞系Brx68s中构建了IFI44L过表达和敲低模型。我们发现，在贴壁的MCF7细胞中，IFI44L OE显著增加STING表达，而在悬浮的循环肿瘤细胞中，IFI44L OE则抑制STING表达。我们观察到IFI44L不影响经典STING信号分子pIRF3和pTBK1。IFI44L调控STING的后果和机制尚不清楚，实验室正在进行实验以解答这些问题；IFI44L的体内研究正在进行，以阐明该基因对肿瘤形成和转移的影响。我们预期IFI44L OE具有抑瘤机制，而IFI44L KO则预期相反。此外，我们计划研究IFI44L对STING的调控及其对免疫逃逸和转移的可能影响。
查看英文原文 English 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 understand the implications of hypoxic memory and suppression of IFI44L, we generated IFI44L overexpression and knockdown models in MCF7 and NT2.5 breast cell lines, and Brx68s, a circulating tumor cell line. We discovered that in adherent MCF7 cells, IFI44L OE significantly increases STING expression, whereas in suspension circulating tumor cells, IFI44L OE suppresses STING expression. We see that IFI44L does not impact canonical STING signaling molecules, pIRF3 and pTBK1. The consequences and mechanisms of STING regulation by IFI44L are unknown and experiments are ongoing in the lab to address these questions; in vivo studies of IFI44L are ongoing to elucidate the impact this gene has on tumor formation and metastasis. We expect to see that IFI44L OE has a tumor suppressive mechanism, and expect the opposite with IFI44L KO. Additionally, we plan to investigate STING regulation by IFI44L and the possible impact that this has on immune evasion and metastasis.
利益披露 Disclosure
R. Marker, None.