PO.MCB04.01 · 分子与细胞生物学
乳酸介导的对管腔型乳腺癌细胞肿瘤内在I型干扰素应答的抑制
Lactate mediated suppression of tumor intrinsic type I interferon response in luminal breast cancer cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
肿瘤缺氧对癌症发展有显著贡献，可促进肿瘤生长和转移。我们实验室此前的工作表明，长期缺氧会导致管腔型乳腺肿瘤细胞内I型干扰素（IFN）信号的显著抑制。值得注意的是，即使将缺氧预培养的细胞重新氧合后，这种抑制仍持续存在，提示存在缺氧记忆。理解IFN通路抑制的基础十分重要，因为IFN信号减弱会削弱抗肿瘤免疫应答，并可促进肿瘤细胞的增殖和存活。已知缺氧还会诱导代谢重编程，导致乳酸积累，使肿瘤微环境（TME）酸化，并作为一种信号代谢物抑制抗肿瘤免疫。虽然乳酸在TME内抑制免疫应答中的作用已得到充分确立，但其在肿瘤细胞内调控干扰素信号中的作用仍知之甚少。在本研究中，我们旨在探究乳酸以肿瘤内在方式介导抑制I型IFN应答的机制。我们发现长期缺氧增加乳酸积累并降低I型IFN信号。我们还观察到，向常氧培养的细胞添加外源性乳酸足以抑制I型IFN信号，而药理学抑制乳酸脱氢酶A（LDHA）活性可在缺氧下恢复IFN信号。最近的发现表明，乳酸可通过组蛋白乳酸化——一种新型表观遗传修饰——直接改变基因表达。然而，其在乳腺癌免疫逃逸中的作用仍在很大程度上未被探索。我们观察到，缺氧下乳酸水平升高与组蛋白乳酸化升高相关。确定组蛋白乳酸化是否改变可增强I型IFN信号抑制因子活性的基因表达，将阐明乳酸介导抑制IFN信号的机制。通过揭示这一机制，我们的发现可能揭示恢复干扰素信号并增强乳腺癌免疫治疗疗效的新治疗策略。
查看英文原文 English abstract
Tumor hypoxia significantly contributes to cancer development, promoting tumor growth and metastasis. Previous work in our lab has shown that long term hypoxia leads to a marked suppression of type I interferon (IFN) signaling within luminal breast tumor cells. Notably, this suppression was persistent even when hypoxic precultured cells were reoxygenated which is indicative of hypoxic memory. Understanding the basis of IFN pathway suppression is important, as diminished IFN signaling weakens antitumor immune response and can promote tumor cell proliferation and survival. Hypoxia is also known to induce metabolic reprogramming which results in lactate accumulation, acidifying the tumor microenvironment (TME), and function as a signaling metabolite that suppresses antitumor immunity. While lactate's role in inhibiting immune response within TME is well established, its role within tumor cells in regulating interferon signaling remains poorly understood. In this study, we aim to explore the mechanisms of lactate mediated suppression of type I IFN response in tumor intrinsic manner. We found that long term hypoxia increases lactate accumulation and reduced type I IFN signaling. We also observed that addition of extracellular lactate to cells cultured under normoxia is sufficient to suppress type I IFN signaling, whereas pharmacological inhibition of lactate dehydrogenase A (LDHA) activity restores IFN signaling in hypoxia. Recent discoveries show that lactate can directly alter gene expression through histone lactylation, a novel epigenetic modification. However, its role in breast cancer immune escape remains largely unexplored. We observed that increased lactate levels under hypoxia correlate with elevated histone lactylation. Determining whether histone lactylation alters gene expression that can enhance the activity of suppressors of type I IFN signaling would elucidate the mechanisms of how lactate mediate suppression of IFN signaling. By uncovering this mechanism, our findings may reveal new therapeutic strategies to restore interferon signaling and enhance immunotherapy efficacy in breast cancer.
利益披露 Disclosure
Y. Nagidi, None.