Pan Xue, Xu Xun, Wang Lixuan, Zhang Siyuan, Chen Yingyao, Yang Rongchun, Chen Xijuan, Cheng Bin, Xia Juan, Ren Xianyue
Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.
Front Oncol. 2023 Jan 27;13:1021262. doi: 10.3389/fonc.2023.1021262. eCollection 2023.
Immunotherapy is effective in a subset of head and neck squamous cell carcinoma (HNSCC). However, the unfavorable response rate and inadequate biomarkers for stratifying patients have primarily limited its clinical application. Considering transcriptional factors (TFs) play essential roles in regulating immune activity during HNSCC progression, we comprehensively analyzed the expression alterations of TFs and their prognostic values.
Gene expression datasets and clinical information of HNSCC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) repository. Then, Brain abundant membrane attached signal protein 1 (BASP1) was screened out of differentially expressed TFs by univariate and multivariate survival analysis. Tumor immune dysfunction and exclusion (TIDE) was applied to analyze the response to immunotherapy of BASP1 patients. Meanwhile, GO, KEGG and GSEA analyses were used to enrich the pathways between the BASP1 and BASP1 groups. Single-sample gene set enrichment analysis (ssGSEA), CIBERSORT, EPIC and quanTiseq algorithms were applied to explore immune infiltrations. Also, immune cycle analysis was conducted by ssGSEA. Additionally, lipid peroxidation, glutathione and reactive oxygen species were performed to detect the ferroptosis alternations.
BASP1 was upregulated and associated with poor survival in HNSCC patients. BASP1 patients exhibited better response rates to anti-PD-1 immunotherapy and higher expressions of immune checkpoint inhibitors. GO, KEGG and GSEA analyses indicated that the expression of BASP1 was related to several immune-related pathways and immunogenic ferroptosis signature. The infiltration of activated CD8 T cells was authenticated to be decreased in BASP1 patients. Furthermore, BASP1 was identified to be positively correlated with T cell dysfunction and immune escape. Moreover, silencing BASP1 triggered ferroptosis in HNSCC cells, representing as increased LDH, lipid peroxidation and ROS levels, and reduced glutathione synthesis.
We demonstrated that BASP1 suppressed immunogenic ferroptosis to induce immunosuppressive tumor microenvironment. BASP1 plays a critical role in immune response, and might be a promising classifier for selecting HNSCC patients who benefit from current immunotherapy.
免疫疗法在一部分头颈部鳞状细胞癌（HNSCC）患者中有效。然而，不良反应率以及用于患者分层的生物标志物不足，主要限制了其临床应用。鉴于转录因子（TFs）在HNSCC进展过程中调节免疫活性方面发挥着重要作用，我们全面分析了TFs的表达变化及其预后价值。
从癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）中获取HNSCC的基因表达数据集和临床信息。然后，通过单因素和多因素生存分析，从差异表达的TFs中筛选出脑富集膜附着信号蛋白1（BASP1）。应用肿瘤免疫功能障碍与排除（TIDE）分析BASP1患者对免疫疗法的反应。同时，使用基因本体（GO）、京都基因与基因组百科全书（KEGG）和基因集富集分析（GSEA）来富集BASP1高表达组和低表达组之间的通路。应用单样本基因集富集分析（ssGSEA）、CIBERSORT、EPIC和quanTiseq算法来探索免疫浸润情况。此外，通过ssGSEA进行免疫循环分析。另外，检测脂质过氧化、谷胱甘肽和活性氧物种以检测铁死亡的变化。
BASP1在HNSCC患者中上调，且与不良生存相关。BASP1患者对抗PD - 1免疫疗法表现出更好的反应率以及更高的免疫检查点抑制剂表达。GO、KEGG和GSEA分析表明，BASP1的表达与多种免疫相关通路和免疫原性铁死亡特征有关。经证实，BASP1患者中活化的CD8 T细胞浸润减少。此外，BASP1被确定与T细胞功能障碍和免疫逃逸呈正相关。而且，沉默BASP1会引发HNSCC细胞中的铁死亡，表现为乳酸脱氢酶（LDH）、脂质过氧化和活性氧水平升高，以及谷胱甘肽合成减少。
我们证明BASP1抑制免疫原性铁死亡以诱导免疫抑制性肿瘤微环境。BASP1在免疫反应中起关键作用，可能是选择能从当前免疫疗法中获益的HNSCC患者的有前景的分类标志物。
