Peng Han, Pan Yuwei, Sun Yixin, Wang Xuesong, Fan Xue, Wang Yajuan, Zhao Lintao, Li Xi, Dong Yan, Chen Jianfang, Zhou Jie, Du Yun, Yu Qing, Yang Yongtao, Zhang Yue, Li Jianjun, Liang Houjie, Huang Shuo
Department of Oncology and Southwest Cancer Centre, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Department of Gastroenterology, School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, China.
J Immunother Cancer. 2025 Jun 22;13(6):e011310. doi: 10.1136/jitc-2024-011310.
The treatment of colorectal cancer liver metastasis (CRLM), a leading cause of mortality in patients with colorectal cancer, is complicated by type 2 diabetes (T2D). This study aimed to investigate the CRLM immune microenvironment in the context of T2D and identify potential therapeutic targets.
A hyperglycemic CRLM mouse model was established. Seven single-cell RNA sequencing datasets were analyzed, including three peripheral blood mononuclear cells (PBMCs) datasets (from healthy donors and T2D patients) and four datasets with 20 CRLM samples and matching PBMCs datasets, to explore the immune characteristics and remodeling of the tumor microenvironment in CRLM with concurrent T2D.
CD8T cells exhibited dysfunction and exhaustion in liver metastasis from patients with CRLM and T2D; the proportions of various CD4T cell subpopulations were also altered, and the number of myeloid cells and their function was increased. Myeloid cells in CRLM from patients with T2D exhibited high expression levels of CCL3, which recruited peripheral blood monocytes expressing high levels of CCR1, leading to an accumulation of myeloid cells and an immunosuppressive tumor microenvironment. Recruited cells exhibited enhanced T cell communication abilities, indicating an augmented immunosuppressive capacity. In addition, CCR1 expression in peripheral blood monocytes from patients with CRLM was closely correlated with the immunosuppressive tumor microenvironment, suggesting that CCR1 expression levels may predict immune cell phenotype and prognosis in patients with CRLM and T2D.
Our study revealed complex changes in the tumor microenvironment of patients with CRLM and T2D. In particular, a novel mechanism was identified by which hyperglycemia regulates immunosuppression: the CCL3-CCR1 signaling axis. This finding offers a novel potential therapeutic target for patients with CRLM and T2D and provides an important theoretical basis for the future prediction of the prognosis of these patients.
结直肠癌肝转移（CRLM）是结直肠癌患者死亡的主要原因，2型糖尿病（T2D）会使CRLM的治疗变得复杂。本研究旨在探讨T2D背景下CRLM的免疫微环境，并确定潜在的治疗靶点。
建立了高血糖CRLM小鼠模型。分析了7个单细胞RNA测序数据集，包括3个外周血单核细胞（PBMC）数据集（来自健康供体和T2D患者）以及4个包含20个CRLM样本和匹配PBMC数据集的数据集，以探索合并T2D的CRLM中肿瘤微环境的免疫特征和重塑。
在CRLM和T2D患者的肝转移中，CD8T细胞表现出功能障碍和耗竭；各种CD4T细胞亚群的比例也发生了改变，髓系细胞数量及其功能增加。T2D患者CRLM中的髓系细胞表现出高水平的CCL3表达，其招募了表达高水平CCR1的外周血单核细胞，导致髓系细胞积聚和免疫抑制性肿瘤微环境的形成。招募的细胞表现出增强的T细胞通讯能力，表明免疫抑制能力增强。此外，CRLM患者外周血单核细胞中的CCR1表达与免疫抑制性肿瘤微环境密切相关，这表明CCR1表达水平可能预测CRLM和T2D患者的免疫细胞表型和预后。
我们的研究揭示了CRLM和T2D患者肿瘤微环境的复杂变化。特别是，发现了一种高血糖调节免疫抑制的新机制：CCL3-CCR1信号轴。这一发现为CRLM和T2D患者提供了一个新的潜在治疗靶点，并为未来预测这些患者的预后提供了重要的理论依据。
