PO.IM02.06 · 免疫学
C118S介导的KRAS G12D突变氧化还原调节重编程免疫代谢以抑制肥胖驱动的胰腺肿瘤发生
C118S-mediated redox modulation of KRASG12D mutation reprograms immunometabolism to suppress obesity-driven pancreatic tumorigenesis
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摘要 Abstract
中文摘要
背景：胰腺导管腺癌（PDAC）常由致癌性KRAS G12D/+驱动，并被肥胖诱导的代谢炎症加剧，从而驱动免疫抑制和代谢重编程。全球肥胖和PDAC发病率的同步上升要求制定专门针对肥胖相关KRAS突变肿瘤独特生物学特性的机制性策略。KRAS在半胱氨酸118（C118）处的氧化还原敏感性调节在信号活性中起关键作用，而突变为丝氨酸（C118S）已在其他肿瘤模型中被证明可减弱KRAS功能。然而，C118S对KRAS G12D/+驱动的PDAC免疫代谢景观的影响，尤其是在肥胖背景下，仍未被探索。本研究旨在表征C118S突变如何改变肥胖与瘦型PDAC环境中的免疫和代谢动态。
方法与结果：使用自建的基因工程小鼠模型（KC（KrasCre）背景下的KRAS G12D/+和KRAS G12D+C118S/+），喂食高脂或标准正常饮食以检查肿瘤进展。我们发现KRAS-G12D等位基因中与C118S修饰相关的改变减缓了PDAC的进展。H&E染色显示高级别PanIN病变减少。阿尔辛蓝和天狼星红染色显示黏蛋白产生和纤维化显著减少，表明促纤维增生反应减轻。Ki67免疫组织化学显示细胞增殖减少，CK19染色证实导管标志物表达降低，MIST1染色表明腺泡细胞身份得以保留。我们还检查了相关的免疫浸润（CD8⁺ T细胞、PD-1/PD-L1、髓系细胞）、代谢标志物（GLUT1、CPT1A）。我们发现KRAS G12D+C118S/+肿瘤具有改善的TIME抗肿瘤免疫和代谢特征成分，尤其在肥胖条件下。阐明了将KRAS G12D+C118S/+与免疫-代谢重编程联系起来的氧化还原依赖机制。我们量化了ROS和GTP结合的KRAS活性，以及下游信号传导（PI3K/AKT/mTOR、ERK）。我们发现C118S降低了ROS依赖的KRAS活性、抑制了致癌信号传导，并恢复了代谢免疫适应性。
结论：本研究通过结合基于氧化还原的KRAS突变、代谢应激（肥胖）和免疫代谢信号传导，在胰腺癌研究中开创了一种范式转变。它旨在表明靶向KRAS氧化还原调节可重塑免疫-代谢微环境以阻碍肿瘤进展。研究发现可能带来针对肥胖相关KRAS驱动癌症的新型氧化还原-免疫代谢治疗策略。
查看英文原文 English abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is frequently driven by oncogenic KRAS G12D/+ and exacerbated by obesity-induced metabolic inflammation, driving immune suppression and metabolic reprogramming. The concurrent rise in global obesity and PDAC incidence demands mechanistic strategies specifically tailored to the unique biology of obesity-associated KRAS-mutant tumors. Redox-sensitive regulation of KRAS at cysteine118 (C118) plays a critical role in signaling activity, and mutation to serine (C118S) has been shown to attenuate KRAS function in other tumor models. However, the impact of C118S on the immunometabolism landscape of KRAS G12D/+ driven PDAC particularly in the context of obesity remains unexplored. This study aims to characterize how the C118S mutation alters immune and metabolic dynamics in obese versus lean PDAC settings.
Methods &
Results: Using in-house genetically engineered mouse models (KRAS G12D/+ and KRAS G12D+C118S/+ on a KC (KrasCre) background) fed with high-fat or standard normal diets to examine tumor progression. We found changes related to the C118S modification in the KRAS-G12D allele slowed the progression of PDAC. H&E staining showed reduced high-grade PanIN lesion. Alcian Blue and Sirius Red staining revealed a marked reduction in mucin production and fibrosis, indicating an alleviation of the desmoplastic response. Immunohistochemistry for Ki67 showed decreased cell proliferation, CK19 staining confirmed reduced ductal marker expression, and MIST1 staining indicated preservation of acinar cell identity. We also examined the related immune infiltration (CD8⁺ T cells, PD-1/PD-L1, myeloid cells), metabolic markers (GLUT1, CPT1A). We found that KRAS G12D+C118S/+ tumors had improved antitumor Immune and Metabolic profile components of TIME, particularly under obese conditions. Elucidating the redox-dependent mechanisms linking KRAS G12D+C118S/+ to immune-metabolic reprogramming. We quantified ROS and GTP-bound KRAS activity, and downstream signaling (PI3K/AKT/mTOR, ERK). We found that C118S reduced ROS-dependent KRAS activity, suppresses oncogenic signaling, and restore metabolic immune fitness.
Conclusion: This study pioneers a paradigm shift in pancreatic cancer research by combining redox-based KRAS mutation, metabolic stress (obesity), and immunometabolism signaling. It aims to show that targeting KRAS redox regulation can reshape the immune-metabolic microenvironment to impede tumor progression. Findings could lead to novel redox-immunometabolism therapeutic strategies for obesity-associated KRAS-driven cancers.
利益披露 Disclosure
Z. Rafiq, None..
W. Lu, None.