Leite-Gomes Eduarda, Silva Mariana C, Dias Ana M, Fernandes Ângela, Faria Guilherme, Nogueira Rafaela, Santos-Pereira Beatriz, Fernandes-Mendes Henrique, Azevedo Catarina M, Raposo Joana, López Portero Julian, de Alda Catalá Tania, Taxonera Carlos, Lago Paula, Fernandez-Aceñero Maria J, Rosa Isadora, Marcos-Pinto Ricardo, Pinho Salomé S
Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal.
School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal.
J Crohns Colitis. 2025 Apr 4;19(4). doi: 10.1093/ecco-jcc/jjaf043.
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, established as a risk factor for colorectal cancer (CRC) development. Long-standing inflammation appears to play a central role in colitis-associated colorectal cancer (CAC). However, the molecular mechanism underlying CAC progression is still elusive. Previous evidence showed that levels of branched glycosylation regulate T-cell-mediated immune response associated with IBD severity. Here, we revealed that colonic T cells from IBD patients are dynamically regulated by branched N-glycosylation and associated with the risk of CAC development.
We performed in silico analysis for glycome and immune profile of a publicly available human dataset of CAC patients. Additionally, in a well-characterized cohort of CAC patients, we evaluated the N-glycosylation profile of infiltrated colonic immune cells at different stages of carcinogenesis (colitis, dysplasia and cancer). In vivo studies were conducted in Mgat5 KO mice, using AOM/DSS model to induce CAC. Tumor development and colonic T cells glycoprofile were characterized during CAC development.
The combined analysis of human IBD and CAC clinical samples, together with glycoengineered mouse model susceptible to CAC, revealed a gradual and dynamic increase of branched N-glycans in T cells from colitis to dysplasia and cancer. This glycosylation switch was shown to impose inhibitory properties in T cells, precluding an effective antitumor immune response. Mechanistically, we demonstrated that the deletion of branched N-glycans in Mgat5 knockout mice led to CAC suppression due to increased infiltration of CD8+and γδ T cells, contributing to an effective antitumor immune response. From the clinical standpoint, we demonstrated that branched N-glycosylation levels detected in inflamed lesions from IBD patients predicted CAC progression with a sensitivity of 83.3% and specificity of 67.9% when assessed together with age at diagnosis.
Overall, we here disclosed a new mechanism underlying CAC development, identifying a potential clinical biomarker plausible to improve the efficacy of cancer surveillance programs through the early identification of high-risk IBD patients, for preventive clinical and therapeutic strategies.
炎症性肠病（IBD）是一种胃肠道慢性炎症性疾病，已被确认为结直肠癌（CRC）发生的危险因素。长期炎症似乎在结肠炎相关结直肠癌（CAC）中起核心作用。然而，CAC进展的分子机制仍不清楚。先前的证据表明，分支糖基化水平调节与IBD严重程度相关的T细胞介导的免疫反应。在此，我们揭示了IBD患者的结肠T细胞受分支N-糖基化动态调节，并与CAC发生风险相关。
我们对公开可用的CAC患者人类数据集的糖组和免疫谱进行了计算机分析。此外，在一个特征明确的CAC患者队列中，我们评估了致癌不同阶段（结肠炎、发育异常和癌症）浸润结肠免疫细胞的N-糖基化谱。使用AOM/DSS模型诱导CAC，在Mgat5基因敲除小鼠中进行体内研究。在CAC发展过程中对肿瘤发生和结肠T细胞糖蛋白谱进行了表征。
对人类IBD和CAC临床样本以及易患CAC的糖工程小鼠模型的联合分析显示，从结肠炎到发育异常再到癌症，T细胞中分支N-聚糖逐渐动态增加。这种糖基化转换显示出对T细胞具有抑制特性，排除了有效的抗肿瘤免疫反应。从机制上讲，我们证明Mgat5基因敲除小鼠中分支N-聚糖的缺失导致CAC受到抑制，这是由于CD8 +和γδ T细胞浸润增加，有助于产生有效的抗肿瘤免疫反应。从临床角度来看，我们证明，在IBD患者炎症病变中检测到的分支N-糖基化水平与诊断时的年龄一起评估时，预测CAC进展的敏感性为83.3%，特异性为67.9%。
总体而言，我们在此揭示了CAC发生的一种新机制，确定了一种潜在的临床生物标志物，通过早期识别高危IBD患者，有望改善癌症监测计划的疗效，用于预防性临床和治疗策略。
