重庆大学附属肿瘤医院一期病房;重庆医科大学免疫创新与转化研究院;陆军军医大学基础医学院免疫学教研室;
目的 探讨黑色素瘤细胞鲨烯环氧合酶(SQLE)基因敲除调控肿瘤微环境T细胞浸润影响机体抗肿瘤效应的作用及其分子机制。方法 使用SQLE敲除的B16F10细胞系分别接种免疫完全和免疫缺陷小鼠，明确基因敲除对肿瘤细胞恶性表型的自主和非自主性调控，进一步使用抗体阻断、Luminex多因子检测和流式细胞等技术探索SQLE基因敲除对细胞因子/趋化因子分泌及免疫浸润的影响，结合生物信息学分析，验证SQLE表达与免疫浸润和临床预后的相关性。结果 与免疫缺陷型小鼠相比，敲除SQLE显著抑制免疫完全小鼠肿瘤增殖，延长小鼠生存期。SQLE敲除诱导肿瘤细胞分泌细胞因子和趋化因子，增加肿瘤微环境CD8~+ T细胞浸润从而改善机体抗肿瘤效应。生物信息学分析提示SQLE及其对应的免疫浸润标志物与黑色素瘤患者临床预后明显相关。结论 SQLE通过细胞因子和趋化因子调控肿瘤微环境参与机体抗肿瘤效应，有望成为新的肿瘤免疫药物靶点和疗效预测分子指标。
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[2] Bejarano L,Jordao M J C,Joyce J A.Therapeutic targeting of the tumor microenvironment[J].Cancer Discov,2021,11(4):933-59.
[3] Zou Y,Zhang H,Bi F,et al.Targeting the key cholesterol biosynthesis enzyme squalene monooxygenase for cancer therapy[J].Front Oncol,2022,12:938502.
[4] Li C,Wang Y,Liu D,et al.Squalene epoxidase drives cancer cell proliferation and promotes gut dysbiosis to accelerate colorectal carcinogenesis[J].Gut,2022,71(11):2253-65.
[5] Mahoney C E,Pirman D,Chubukov V,et al.A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition[J].Nat Commun,2019,10(1):96.
[6] Mellman I,Chen D S,Powles T,et al.The cancer-immunity cycle:indication,genotype,and immunotype[J].Immunity,2023,56(10):2188-205.
[7] Giraldo N A,Sanchez-Salas R,Peske J D,et al.The clinical role of the TME in solid cancer[J].Br J Cancer,2019,120(1):45-53.
[8] Brown D N,Caffa I,Cirmena G,et al.Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer[J].Sci Rep,2016,6:19435.
[9] Wu J,Hu W,Yang W,et al.Knockdown of SQLE promotes CD8+ T cell infiltration in the tumor microenvironment[J].Cell Signal,2024,114:110983.
[10] Plitas G,Rudensky A Y.Regulatory T cells in cancer[J].Annu Rev Cancer Biol,2020,4:459-77.
[11] Lunardi S,Lim S Y,Muschel R J,et al.IP-10/CXCL10 attracts regulatory T cells:implication for pancreatic cancer[J].Oncoimmunology,2015,4(9):e1027473.
[12] Jun S Y,Brown A J,Chua N K,et al.Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis[J].Gastroenterology,2021,160(4):1194-1207.e28.
[13] Tuluhong D,Gao H,Li X,et al.Squalene epoxidase promotes breast cancer progression by regulating CCNB1 protein stability[J].Exp Cell Res,2023,433(1):113805.
[14] Xu R,Song J,Ruze R,et al.SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway[J].Cell Death Dis,2023,14(8):497.
基本信息:
DOI：10.19405/j.cnki.issn1000-1492.2024.08.005
中图分类号:R739.5
引用信息:
[1]丁瑶,刘雯,廖亦然等.SQLE敲除促进黑色素瘤肿瘤微环境CD8~+ T细胞浸润发挥抗肿瘤效应[J].安徽医科大学学报,2024,59(08):1315-1322.DOI:10.19405/j.cnki.issn1000-1492.2024.08.005.
基金信息:
重庆市自然科学基金创新发展联合基金重点项目(编号：CSTB2023NSCQ-LZX0010);; 国家自然科学基金(编号：81702443)