Raynaud Christophe M, Jabeen Ayesha, Ahmed Eiman I, Hubrack Satanay, Sanchez Apryl, Sherif Shimaa, Al-Shaibi Ahmad A, Lo Bernice, Roelands Jessica, Bedognetti Davide, Hendrickx Wouter
Tumor Biology and Immunology Laboratory, Research Branch, Sidra Medicine, Doha, Qatar.
Department of Biomedical Science, College of Health Sciences, Qatar University, Doha, Qatar.
Front Immunol. 2025 Jan 24;15:1500374. doi: 10.3389/fimmu.2024.1500374. eCollection 2024.
Colorectal cancer (CRC) is a prevalent malignancy with significant morbidity and mortality worldwide. A deeper understanding of the interaction of cancer cells with other cells in the tumor microenvironment is crucial to devise effective therapeutic strategies. MUC2, a major component of the protective mucus layer in the gastrointestinal tract, has been implicated in CRC progression and immune response regulation.
In this study, we sought to elucidate the relationship between MUC2 expression and immune infiltration within CRC using models involving two well-established cell lines, HT-29 and LS-174T. By employing CRISPR-mediated MUC2 knockout, we investigated the influence of MUC2 on tumor immune infiltration and its interplay with T cells and NK cells enriched peripheral blood mononuclear cells (PBMCs) in 3D spheroid cultures.
While MUC2 was more abundant in LS-174T cell line compared to HT-29, its knockout resulted in increased immune infiltration solely in the HT-29 cell line, but not in the LS-174T cell line. We revealed that the removal of MUC2 protein was compensated in LS-174T by the expression of other gel-forming mucin proteins (MUC6, MUC5B) commonly expressed in the gastrointestinal epithelium, while this was not observed in HT-29 cell line.
Our study is the first to demonstrate that MUC2 functions as a physical barrier to immune infiltration in colorectal cancer (CRC) . In HT-29 cells, MUC2 knockout increased immune infiltration, while in LS-174T cells, compensatory expression of other mucins (MUC6, MUC5B) maintained the barrier. These findings reveal the complexity of mucin biology in CRC and suggest that targeting mucin pathways could be a novel therapeutic approach.
结直肠癌（CRC）是一种在全球范围内发病率和死亡率都很高的常见恶性肿瘤。深入了解癌细胞与肿瘤微环境中其他细胞的相互作用对于制定有效的治疗策略至关重要。MUC2是胃肠道保护性黏液层的主要成分，与结直肠癌的进展和免疫反应调节有关。
在本研究中，我们试图通过使用涉及两种成熟细胞系HT-29和LS-174T的模型来阐明MUC2表达与结直肠癌免疫浸润之间的关系。通过采用CRISPR介导的MUC2基因敲除，我们研究了MUC2对肿瘤免疫浸润的影响及其在3D球体培养中与富集外周血单个核细胞（PBMC）的T细胞和NK细胞的相互作用。
虽然与HT-29细胞系相比，MUC2在LS-174T细胞系中更为丰富，但其基因敲除仅导致HT-29细胞系中的免疫浸润增加，而在LS-174T细胞系中则没有。我们发现，在LS-174T中，胃肠道上皮中常见的其他凝胶形成黏蛋白（MUC6、MUC5B）的表达补偿了MUC2蛋白的缺失，而在HT-29细胞系中未观察到这种情况。
我们的研究首次证明MUC2在结直肠癌（CRC）中作为免疫浸润的物理屏障发挥作用。在HT-29细胞中，MUC2基因敲除增加了免疫浸润，而在LS-174T细胞中，其他黏蛋白（MUC6、MUC5B）的补偿性表达维持了屏障作用。这些发现揭示了结直肠癌中黏蛋白生物学的复杂性，并表明靶向黏蛋白途径可能是一种新的治疗方法。
