Yue Guangxing, Tang Jingwen, Zhang Lihan, Niu Hong, Li Huahua, Luo Suxia
Department of Integrated Chinese and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.
Department of Medicine Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China.
J Gastrointest Oncol. 2021 Feb;12(1):38-51. doi: 10.21037/jgo-21-50.
As an immune checkpoint that suppresses antitumor immunity, CD276 is a potential therapeutic target for cancer immunotherapy. However, the role of CD276 in esophageal squamous cell carcinoma (ESCC) has not been thoroughly examined. A greater understanding of the regulatory mechanism of CD276 may improve the clinical response and efficacy of cancer immunotherapy.
The expression of CD276 was measured by qRT-PCR, IHC and flow cytometry analysis. T cell infiltration in ESCC was measured by qRT-PCR and immunofluorescence analysis. The regulation function of CD276 in glucose metabolism was examined by metabolism assays, western blotting and small molecule inhibitors. Transfection was used for gene editing. The oncogenic function of CD276 was examined in vivo by CAR-T cell therapy model.
Based on our findings, CD276 regulated the expression of the gene in ESCC. Overexpression of CD276 induced the phosphorylation of PKM2 by the STAT3 signalling pathway to promote glucose metabolism in tumors. The accumulation of lactic acid in the tumor microenvironment has been reported to regulate the immune cells, particularly CD8+ T cells. We further analyzed the effect of CD276 on the function of T cells. Chimeric antigen receptor T cells (CAR-T) targeting human epidermal growth factor receptor 2 (HER2) were used as effector cells to detect the effect of CD276 on immunotherapy. The therapeutic effects of CAR-T cells were markedly limited by CD276 overexpression.
Our results are the first to show that tumor-derived CD276 supports disease progression. Overexpression of CD276 promoted glucose metabolism in tumor and inhibited the function of CD8+ T cells. Therefore, strategies targeting CD276 might improve the response to cancer immunotherapy of ESCC patients.
作为一种抑制抗肿瘤免疫的免疫检查点，CD276是癌症免疫治疗的一个潜在治疗靶点。然而，CD276在食管鳞状细胞癌（ESCC）中的作用尚未得到充分研究。对CD276调控机制的更深入了解可能会改善癌症免疫治疗的临床反应和疗效。
通过qRT-PCR、免疫组化（IHC）和流式细胞术分析检测CD276的表达。通过qRT-PCR和免疫荧光分析检测ESCC中的T细胞浸润情况。通过代谢分析、蛋白质免疫印迹法和小分子抑制剂研究CD276在葡萄糖代谢中的调控功能。采用转染进行基因编辑。通过CAR-T细胞治疗模型在体内研究CD276的致癌功能。
基于我们的研究结果，CD276在ESCC中调控该基因的表达。CD276的过表达通过STAT3信号通路诱导丙酮酸激酶M2（PKM2）磷酸化，从而促进肿瘤中的葡萄糖代谢。据报道，肿瘤微环境中乳酸的积累可调节免疫细胞，特别是CD8+T细胞。我们进一步分析了CD276对T细胞功能的影响。以人表皮生长因子受体2（HER2）为靶点的嵌合抗原受体T细胞（CAR-T）用作效应细胞，以检测CD276对免疫治疗的影响。CD276的过表达显著限制了CAR-T细胞的治疗效果。
我们的结果首次表明肿瘤来源的CD276促进疾病进展。CD276的过表达促进肿瘤中的葡萄糖代谢并抑制CD8+T细胞的功能。因此，针对CD276的策略可能会改善ESCC患者对癌症免疫治疗的反应。
