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Microbiota-induced S100A11-RAGE axis underlies immune evasion in right-sided colon adenomas and is a therapeutic target to boost anti-PD1 efficacy
Gut ( IF 23.0 ) Pub Date : 2024-09-09 , DOI: 10.1136/gutjnl-2024-332193
Qiming Zhou 1, 2 , Linhan Lei 1 , Junhong Cheng 1 , Junyou Chen 1 , Yuyang Du 1 , Xuehua Zhang 1 , Qing Li 3 , Chuangen Li 4 , Haijun Deng 1 , Chi Chun Wong 5 , Baoxiong Zhuang 6 , Guoxin Li 6, 7 , Xiaowu Bai 6
Affiliation  

Background Tumourigenesis in right-sided and left-sided colons demonstrated distinct features. Objective We aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis. Design Single-cell and spatial transcriptomic datasets were analysed to reveal alterations between right-sided and left-sided colon ADs. Cells, animal experiments and clinical specimens were used to verify the results. Results Single-cell analysis revealed that in right-sided ADs, there was a significant reduction of goblet cells, and these goblet cells were dysfunctional with attenuated mucin biosynthesis and defective antigen presentation. An impairment of the mucus barrier led to biofilm formation in crypts and subsequent bacteria invasion into right-sided ADs. The regions spatially surrounding the crypts with biofilm occupation underwent an inflammatory response by lipopolysaccharide (LPS) and an apoptosis process, as revealed by spatial transcriptomics. A distinct S100A11+ epithelial cell population in the right-sided ADs was identified, and its expression level was induced by bacterial LPS and peptidoglycan. S100A11 expression facilitated tumour growth in syngeneic immunocompetent mice with increased myeloid-derived suppressor cells (MDSC) but reduced cytotoxic CD8+ T cells. Targeting S100A11 with well-tolerated antagonists of its receptor for advanced glycation end product (RAGE) (Azeliragon) significantly impaired tumour growth and MDSC infiltration, thereby boosting the efficacy of anti-programmed cell death protein 1 therapy in colon cancer. Conclusion Our findings unravelled that dysfunctional goblet cells and consequential bacterial translocation activated the S100A11-RAGE axis in right-sided colon ADs, which recruits MDSCs to promote immune evasion. Targeting this axis by Azeliragon improves the efficacy of immunotherapy in colon cancer. Data are available on reasonable request.

中文翻译:


微生物诱导的 S100A11-RAGE 轴是右侧结肠腺瘤免疫逃避的基础,也是增强抗 PD1 功效的治疗靶点



背景 右侧和左侧结肠的肿瘤发生表现出不同的特征。目的 我们旨在描述代表结肠肿瘤发生早期阶段的左侧和右侧腺瘤 (AD) 之间的差异。设计 对单细胞和空间转录组数据集进行分析,以揭示右侧和左侧结肠 AD 之间的变化。利用细胞、动物实验和临床标本来验证结果。结果单细胞分析显示,在右侧 AD 中,杯状细胞显着减少,并且这些杯状细胞功能失调,粘蛋白生物合成减弱,抗原呈递缺陷。粘液屏障受损导致隐窝中形成生物膜,随后细菌侵入右侧 AD。空间转录组学揭示,被生物膜占据的隐窝周围的空间区域经历了脂多糖(LPS)的炎症反应和细胞凋亡过程。在右侧 AD 中鉴定出独特的 S100A11+ 上皮细胞群,其表达水平由细菌 LPS 和肽聚糖诱导。 S100A11 表达促进同基因免疫活性小鼠的肿瘤生长,其骨髓源性抑制细胞 (MDSC) 增加,但细胞毒性 CD8+ T 细胞减少。使用耐受良好的晚期糖基化终末产物 (RAGE) 受体拮抗剂(Azeliragon)靶向 S100A11,可显着削弱肿瘤生长和 MDSC 浸润,从而提高抗程序性细胞死亡蛋白 1 疗法在结肠癌中的疗效。 结论 我们的研究结果表明,功能失调的杯状细胞和随之而来的细菌易位激活了右侧结肠 AD 中的 S100A11-RAGE 轴,该轴招募 MDSC 来促进免疫逃避。 Azeliraragon 靶向该轴可提高结肠癌免疫治疗的疗效。可根据合理要求提供数据。
更新日期:2024-09-10
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