Dai Liyuan, Huang Liling, Li Lin, Tang Le, Shi Yuankai, Han Xiaohong
Department of Medical Oncology, Beijing Key Laboratory of Key Technologies for Early Clinical Trial Evaluation of Innovative Drugs for Major Diseases, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
Respir Res. 2025 Jun 12;26(1):214. doi: 10.1186/s12931-025-03275-w.
This study investigates HDAC3 as a potential immunotherapy biomarker in advanced non-small cell lung cancer (aNSCLC), focusing on its association with treatment response to immune checkpoint inhibitors (ICIs).
We employed a multi-phase approach in 78 aNSCLC patients with 138 plasma samples, starting with a discovery phase that identified differential autoantibodies (AAbs) using proteomic analysis in responders and non-responders. In the validation phase, we assessed AAb levels at multiple time points. Additionally, immunohistochemistry and multiple immunofluorescence ( = 21) were used to validate HDAC3 expression in FFPE samples, single-cell RNA sequencing ( = 26) was performed to explore gene expression differences, cell and animal experiments were performed.
We identified 127 differential AAbs, with five key AAbs (HDAC3, METTL21C, HSPB3, SPACA7, and SPPL2B) consistently linked to prognosis pre- and post-treatment ( < 0.05). A risk score model based on these AAbs effectively predicted progression-free survival. Furthermore, HDAC3 expression correlated with significant pathway enrichments and was associated with higher TGFβ1, PD-L1 infiltration and lower CD8 T cells infiltration ( < 0.05). knockdown significantly inhibited cell proliferation, impaired colony formation, and induced G0/G1 phase arrest in lung cancer cells. Preclinical models demonstrated that RGFP966, an HDAC3 inhibitor, combined with anti–PD-1 therapy enhanced CD8 T cell infiltration ( < 0.05).
Our findings underscore HDAC3’s role as a biomarker for predicting ICI response in aNSCLC and suggest its potential as a therapeutic target, paving the way for future studies on HDAC3-targeted therapies to improve immunotherapy outcomes.
not applicable.
The online version contains supplementary material available at 10.1186/s12931-025-03275-w.
本研究调查组蛋白去乙酰化酶3（HDAC3）作为晚期非小细胞肺癌（aNSCLC）潜在免疫治疗生物标志物的情况，重点关注其与免疫检查点抑制剂（ICI）治疗反应的关联。
我们对78例aNSCLC患者的138份血浆样本采用多阶段方法，首先是探索阶段，通过蛋白质组学分析在应答者和非应答者中鉴定差异自身抗体（AAb）。在验证阶段，我们在多个时间点评估AAb水平。此外，使用免疫组织化学和多重免疫荧光（n = 21）来验证FFPE样本中HDAC3的表达，进行单细胞RNA测序（n = 26）以探索基因表达差异，并进行细胞和动物实验。
我们鉴定出127种差异AAb，其中五种关键AAb（HDAC3、METTL21C、HSPB3、SPACA7和SPPL2B）在治疗前后均与预后持续相关（P < 0.05）。基于这些AAb的风险评分模型有效预测了无进展生存期。此外，HDAC3表达与显著的通路富集相关，并且与更高的转化生长因子β1（TGFβ1）、程序性死亡受体配体1（PD-L1）浸润以及更低的CD8 T细胞浸润相关（P < 0.05）。HDAC3敲低显著抑制肺癌细胞增殖、损害集落形成并诱导G0/G1期阻滞。临床前模型表明，HDAC3抑制剂RGFP966与抗程序性死亡蛋白1（PD-1）疗法联合可增强CD8 T细胞浸润（P < 0.05）。
我们的研究结果强调了HDAC3作为预测aNSCLC中ICI反应生物标志物的作用，并表明其作为治疗靶点的潜力，为未来关于HDAC3靶向疗法以改善免疫治疗结果的研究铺平了道路。
不适用。
在线版本包含可在10.1186/s12931-025-03275-w获取的补充材料。
