ACTA2 Expression Predicts Survival and Is Associated with Response to Immune Checkpoint Inhibitors in Gastric Cancer.
ACTA2 Expression Predicts Survival and Is Associated with Response to Immune Checkpoint Inhibitors in Gastric Cancer.
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DOI：
10.1158/1078-0432.ccr-22-1897
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发表时间：
2023-03-14
影响因子：
11.5
通讯作者：
Hwang, Tae Hyun
中科院分区：
文献类型：
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作者：
Park, Sunho;Karalis, John D.;Hong, Changjin;Clemenceau, Jean R.;Porembka, Matthew R.;Kim, In -Ho;Lee, Sung Hak;Wang, Sam C.;Cheong, Jae-Ho;Hwang, Tae Hyun
我们试图确定预测胃癌患者总生存期和对免疫检查点抑制剂（ICI）反应的生物标志物。这是一项回顾性研究，包括多个独立的胃癌患者队列。肿瘤ACTA 2表达与总生存期和ICI反应之间的关联在其肿瘤用批量mRNA测序分析的患者中确定。单细胞RNA测序和数字空间分析数据用于比较来自对ICI有反应和无反应的胃癌患者的肿瘤。在567例患者发现队列中，肿瘤ACTA 2表达增加与总生存期变差独立相关（HR：1.28/单位增加，95%CI：1.02-1.62）。这一发现在三个独立队列中得到验证（n=974; HR：1.52/单位增加，95%CI：1.34-1.73）。在接受ICI治疗的108例患者中，56%的ACTA 2低表达患者对ICI有反应，而ACTA 2高表达患者的反应率为25%（p=0.004）。在对5名接受ICI治疗的微卫星不稳定性高的患者的公开可用的单细胞RNA测序数据集的分析中，对ICI有反应的患者的肿瘤基质ACTA 2表达低于4名无反应者。来自4例ICI缓解者和5例ICI非缓解者的肿瘤样本的数字空间分析显示，缓解者在α-SMA阳性癌症相关成纤维细胞中的ACTA 2表达可能低于非缓解者（中位数：5.00 vs. 5.50）。ACTA 2表达与胃癌患者的生存率和ICI反应相关。ACTA 2在癌症相关成纤维细胞中的表达，而不是在其他细胞区室中的表达，似乎与ICI反应有关。
We sought to identify biomarkers that predict overall survival and response to immune checkpoint inhibitors (ICI) for gastric cancer patients. This was a retrospective study of multiple independent cohorts of gastric cancer patients. The association between tumor ACTA2 expression and overall survival and ICI response were determined in patients whose tumors were analyzed with bulk mRNA sequencing. Single cell RNA-sequencing and digital spatial profiling data were used to compare tumors from gastric cancer patients who did and did not respond to ICI. Increasing tumor ACTA2 expression was independently associated with worse overall survival in a 567-patient discovery cohort (HR: 1.28 per unit increase, 95%CI: 1.02–1.62). This finding was validated in three independent cohorts (n=974; HR: 1.52 per unit increase, 95%CI: 1.34–1.73). Of the 108 patients treated with ICI, 56% of patients with low ACTA2 expression responded to ICI versus 25% of patients with high ACTA2 expression (p=0.004). In an analysis of a publicly available single cell RNA-sequencing dataset of 5 microsatellite instability-high patients treated with ICI, the patient who responded to ICI had lower tumor stromal ACTA2 expression than the 4 non-responders. Digital spatial profiling of tumor samples from 4 ICI responders and 5 ICI non-responders revealed that responders may have lower ACTA2 expression in α-SMA-positive cancer-associated fibroblasts than non-responders (median: 5.00 vs. 5.50). ACTA2 expression is associated with survival and ICI response in gastric cancer patients. ACTA2 expression in cancer-associated fibroblasts, but not in other cellular compartments, appears to be associated with ICI response.