Reduced Number and Immune Dysfunction of CD4+ T Cells in Obesity Accelerate Colorectal Cancer Progression.
Reduced Number and Immune Dysfunction of CD4+ T Cells in Obesity Accelerate Colorectal Cancer Progression.
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肥胖是多种癌症的已知危险因素，它会减少肿瘤免疫微环境中细胞毒性免疫细胞的数量和功能（TIME）。然而，肥胖对CD4+ T细胞的影响尚不清楚。因此，本研究旨在阐明肥胖对TIME期CD4+ T细胞的影响。采用45%高脂饲料（HFD）喂养，接种结肠癌细胞系MC38，建立荷瘤肥胖小鼠模型。与对照组相比，肿瘤生长明显加快。肿瘤CD4+ T细胞数量明显减少，程序性死亡-1 （PD-1）表达增加，CD107a表达减少，IFN-γ、TNF-α等细胞因子产生减少，提示功能障碍。我们进一步建立了CD4+ T细胞缺失的hfd喂养模型小鼠，其肿瘤浸润减少，CD8+ T细胞中PD-1表达增加，肥胖诱导的肿瘤生长以CD4+ T细胞依赖的方式加速。这些发现表明，肥胖导致CD4+ T细胞数量减少和功能障碍导致CD4+和CD8+ T细胞抗肿瘤反应下降，最终加速结直肠癌的进展。我们的发现可能阐明与肥胖相关的结直肠癌预后不良的发病机制。
Obesity, a known risk factor for various types of cancer, reduces the number and function of cytotoxic immune cells in the tumor immune microenvironment (TIME). However, the impact of obesity on CD4+ T cells remains unclear. Therefore, this study aimed to clarify the impact of obesity on CD4+ T cells in the TIME. A tumor-bearing obese mouse model was established by feeding with 45% high-fat diet (HFD), followed by inoculation with a colon cancer cell line MC38. Tumor growth was significantly accelerated compared to that in mice fed a control diet. Tumor CD4+ T cells showed a significant reduction in number and an increased expression of programmed death-1 (PD-1), and decreased CD107a expression and cytokine such as IFN-γ and TNF-α production, indicating dysfunction. We further established CD4+ T cell-depleted HFD-fed model mice, which showed reduced tumor infiltration, increased PD-1 expression in CD8+ T cells, and obesity-induced acceleration of tumor growth in a CD4+ T cell-dependent manner. These findings suggest that the reduced number and dysfunction of CD4+ T cells due to obesity led to a decreased anti-tumor response of both CD4+ and CD8+ T cells to ultimately accelerate the progression of colorectal cancer. Our findings may elucidate the pathogenesis for poor outcomes of colorectal cancer associated with obesity.
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DOI：
10.1136/bmj.j477
发表时间：
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