Lee Hansong, Ko Dai Sik, Heo Hye Jin, Baek Seung Eun, Kim Eun Kyoung, Kwon Eun Jung, Kang Junho, Yu Yeuni, Baryawno Ninib, Kim Kihun, Lee Dongjun, Kim Yun Hak
Medical Research Institute, Pusan National University, Yangsan, Republic of Korea.
Division of Vascular Surgery, Department of General Surgery, Gachon University College of Medicine, Gil Medical Center, Incheon, Republic of Korea.
PLoS One. 2025 Jan 3;20(1):e0315981. doi: 10.1371/journal.pone.0315981. eCollection 2025.
The identification of immune environments and cellular interactions in the colon microenvironment is essential for understanding the mechanisms of chronic inflammatory disease. Despite occurring in the same organ, there is a significant gap in understanding the pathophysiology of ulcerative colitis (UC) and colorectal cancer (CRC). Our study aims to address the distinct immunopathological response of UC and CRC. Using single-cell RNA sequencing datasets, we analyzed the profiles of immune cells in colorectal tissues obtained from healthy donors, UC patients, and CRC patients. The colon tissues from patients and healthy participants were visualized by immunostaining followed by laser confocal microscopy for select targets. Natural killer (NK) cells from UC patients on medication showed reduced cytotoxicity compared to those from healthy individuals. Nonetheless, a UC-specific pathway called the BAG6-NCR3 axis led to higher levels of inflammatory cytokines and increased the cytotoxicity of NCR3+ NK cells, thereby contributing to the persistence of colitis. In the context of colorectal cancer (CRC), both NK cells and CD8+ T cells exhibited significant changes in cytotoxicity and exhaustion. The GALECTIN-9 (LGALS9)-HAVCR2 axis was identified as one of the CRC-specific pathways. Within this pathway, NK cells solely communicated with myeloid cells under CRC conditions. HAVCR2+ NK cells from CRC patients suppressed NK cell-mediated cytotoxicity, indicating a reduction in immune surveillance. Overall, we elucidated the comprehensive UC and CRC immune microenvironments and NK cell-mediated immune responses. Our findings can aid in selecting therapeutic targets that increase the efficacy of immunotherapy.
识别结肠微环境中的免疫环境和细胞相互作用对于理解慢性炎症性疾病的机制至关重要。尽管溃疡性结肠炎（UC）和结直肠癌（CRC）发生在同一器官，但在理解它们的病理生理学方面仍存在显著差距。我们的研究旨在解决UC和CRC不同的免疫病理反应。利用单细胞RNA测序数据集，我们分析了从健康供体、UC患者和CRC患者获得的结直肠组织中免疫细胞的图谱。通过免疫染色，然后对选定靶点进行激光共聚焦显微镜观察，对患者和健康参与者的结肠组织进行可视化。与健康个体相比，正在接受药物治疗的UC患者的自然杀伤（NK）细胞表现出细胞毒性降低。尽管如此，一条名为BAG6-NCR3轴的UC特异性通路导致炎症细胞因子水平升高，并增加了NCR3+NK细胞的细胞毒性，从而导致结肠炎持续存在。在结直肠癌（CRC）的背景下，NK细胞和CD8+T细胞在细胞毒性和耗竭方面均表现出显著变化。半乳糖凝集素-9（LGALS9）-甲型肝炎病毒细胞受体2（HAVCR2）轴被确定为CRC特异性通路之一。在这条通路中，在CRC条件下，NK细胞仅与髓样细胞相互作用。CRC患者的HAVCR2+NK细胞抑制了NK细胞介导的细胞毒性，表明免疫监视功能降低。总体而言，我们阐明了UC和CRC的综合免疫微环境以及NK细胞介导的免疫反应。我们的研究结果有助于选择提高免疫治疗疗效的治疗靶点。
