Hwang Sung-Hyun, Yang Yeseul, Jung Jae-Ha, Kim Jin Won, Kim Yongbaek
Laboratory of Clinical Pathology, College of Veterinary Medicine, Seoul National University, 1 Gwanak-Ro, Gwanak-Gu, Seoul, 08826, Korea.
BK21 Future Veterinary Medicine Leading Education and Research Center, College of Veterinary Medicine, Seoul National University, 1 Gwanak-Ro, Gwanak-Gu, Seoul, 08826, Korea.
Cell Biosci. 2024 Nov 14;14(1):137. doi: 10.1186/s13578-024-01308-3.
Within the tumor microenvironment, altered lipid metabolism promotes cancer cell malignancy by activating oncogenic cascades; however, impact of lipid metabolism in CD4 tumor-infiltrating lymphocytes (TILs) remains poorly understood. Here, we elucidated that role of stearoyl-CoA desaturase (SCD) increased by treatment with cancer-associated fibroblast (CAF) supernatant in CD4 T cells on their subset differentiation and activity of CD8 T cells.
In our study, we observed that CD4 TILs had higher lipid droplet content than CD4 splenic T cells. In tumor tissue, CAF-derived supernatant provided fatty acids to CD4 TILs, which increased the expression of SCD and oleic acid (OA) content. Increased SCD expression by OA treatment enhanced the levels of Th1 cell markers TBX21, interleukin-2, and interferon-γ. However, SCD inhibition upregulated the expression of regulatory T (Treg) cell markers, FOXP3 and transforming growth factor-β. Comparative fatty acid analysis of genetically engineered Jurkat cells revealed that OA level was significantly higher in SCD-overexpressing cells. Overexpression of SCD increased expression of Th1 cell markers, while treatment with OA enhanced the transcriptional level of TBX21 in Jurkat cells. In contrast, palmitic acid which is higher in SCD-KO cells than other subclones enhanced the expression of Treg cell markers through upregulation of mitochondrial superoxide. Furthermore, SCD increased the secretion of the C-X-C motif chemokine ligand 11 (CXCL11) from CD4 T cells. The binding of CXCL11 to CXCR3 on CD8 T cells augmented their cytotoxic activity. In a mouse tumor model, the suppressive effect of CD8 T cells on tumor growth was dependent on CXCR3 expression.
These findings illustrate that SCD not only orchestrates the differentiation of T helper cells, but also promotes the antitumor activity of CD8 T cells, suggesting its function in adverse tumor microenvironments.
在肿瘤微环境中，脂质代谢改变通过激活致癌级联反应促进癌细胞恶性发展；然而，脂质代谢在CD4肿瘤浸润淋巴细胞（TILs）中的作用仍知之甚少。在此，我们阐明了用癌相关成纤维细胞（CAF）上清液处理后CD4 T细胞中硬脂酰辅酶A去饱和酶（SCD）增加对其亚群分化及CD8 T细胞活性的作用。
在我们的研究中，我们观察到CD4 TILs的脂滴含量高于CD4脾T细胞。在肿瘤组织中，CAF来源的上清液为CD4 TILs提供脂肪酸，这增加了SCD的表达和油酸（OA）含量。OA处理增加SCD表达提高了Th1细胞标志物TBX21、白细胞介素-2和干扰素-γ的水平。然而，SCD抑制上调了调节性T（Treg）细胞标志物FOXP3和转化生长因子-β的表达。对基因工程Jurkat细胞的脂肪酸分析表明，SCD过表达细胞中的OA水平显著更高。SCD过表达增加了Th1细胞标志物的表达，而OA处理增强了Jurkat细胞中TBX21的转录水平。相反，SCD基因敲除（KO）细胞中高于其他亚克隆的棕榈酸通过上调线粒体超氧化物增强了Treg细胞标志物的表达。此外，SCD增加了CD4 T细胞中C-X-C基序趋化因子配体11（CXCL11）的分泌。CXCL11与CD8 T细胞上的CXCR3结合增强了它们的细胞毒性活性。在小鼠肿瘤模型中，CD8 T细胞对肿瘤生长的抑制作用依赖于CXCR3表达。
这些发现表明，SCD不仅协调辅助性T细胞的分化，还促进CD8 T细胞的抗肿瘤活性，提示其在不良肿瘤微环境中的作用。
