Fan Tianyu, Wan Yi, Niu Delei, Wang Bin, Zhang Bei, Zhang Zugui, Zhang Yue, Gong Zheng, Zhang Li
The Department of Immunology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, Shandong, China.
The Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, 308 Ningxia Road, Qingdao, Shandong, China.
Discov Oncol. 2022 Mar 10;13(1):13. doi: 10.1007/s12672-022-00474-5.
Glioma is the most common intracranial malignancy with a poor prognosis. Although remarkable advances have been made in the study of diagnostic and prognostic biomarkers, the efficacy of current treatment strategies is still unsatisfactory. Therefore, developing novel and reliable targets is desperately needed for glioma patients. Pyroptosis reshapes tumor immune microenvironment (TME) and promotes the destruction of the tumor by the immune system. Moreover, pyroptosis levels correlate with prognosis and immunotherapy response in many cancer patients. This study performed a comprehensive analysis of pyroptosis in the glioma, unveiling its potential value in glioma prognosis prediction and therapy efficacy.
Firstly, the pyroptosis regulation patterns were comprehensively evaluated on 33 pyroptosis-related genes in 1716 glioma samples. The correlations were analyzed between pyroptosis regulation patterns and TME immune cell infiltration properties. Next, pyroptosis regulation patterns were measured by the PSscore model based on principal component analysis algorithms. The correlations were analyzed between PSscore and tumor mutational burden (TMB), immune checkpoint blockade (ICB) therapeutic advantages. Last, the findings were validated in an independently collected external clinical cohort.
We determined two distinct pyroptosis regulation patterns. The cluster-A was high immune cell infiltration with a poor prognosis (p < 0.001), whereas the cluster-B was low immune cell infiltration with a better prognosis (p < 0.001). We developed the PSscore as a measure for pyroptosis regulation patterns. The high PSscore with an inflamed TME phenotype, a high TMB (p < 0.0001), increased innate immune response, and a poor prognosis (p < 0.001). It was in stark contrast to the low PSscore (p < 0.001). Analysis of PSscore with checkpoint therapy indicated high PSscore were correlated with enhanced response to anti-PD-1 immunotherapy (p = 0.0046). For validation, we utilized in vitro experiments on an external clinical cohort. The results demonstrated that GSDMD expression level in the high PSscore group was significantly upregulated compared to the low PSscore group (p < 0.001); the CD3+ T cells and the CD3+PD-1+ cells significantly increased in the high PSscore group compared to the low PSscore group (p < 0.01).
The PSscore of pyroptosis regulation pattern is a reliable biomarker, and it is valuable to predict prognosis, TME, and ICB therapeutic efficiency in glioma patients.
胶质瘤是最常见的颅内恶性肿瘤，预后较差。尽管在诊断和预后生物标志物的研究方面取得了显著进展，但当前治疗策略的疗效仍不尽人意。因此，胶质瘤患者迫切需要开发新的可靠靶点。细胞焦亡可重塑肿瘤免疫微环境（TME），并促进免疫系统对肿瘤的破坏。此外，细胞焦亡水平与许多癌症患者的预后和免疫治疗反应相关。本研究对胶质瘤中的细胞焦亡进行了全面分析，揭示了其在胶质瘤预后预测和治疗疗效方面的潜在价值。
首先，对1716例胶质瘤样本中的33个细胞焦亡相关基因的细胞焦亡调控模式进行了全面评估。分析了细胞焦亡调控模式与TME免疫细胞浸润特性之间的相关性。接下来，基于主成分分析算法，通过PSscore模型测量细胞焦亡调控模式。分析了PSscore与肿瘤突变负荷（TMB）、免疫检查点阻断（ICB）治疗优势之间的相关性。最后，在独立收集的外部临床队列中对研究结果进行了验证。
我们确定了两种不同的细胞焦亡调控模式。A组免疫细胞浸润高，预后差（p<0.001），而B组免疫细胞浸润低，预后较好（p<0.001）。我们开发了PSscore作为细胞焦亡调控模式的一种度量。高PSscore与炎症性TME表型、高TMB（p<0.0001）、先天免疫反应增加和预后差（p<0.001）相关。这与低PSscore形成鲜明对比（p<0.001）。PSscore与检查点治疗的分析表明，高PSscore与抗PD-1免疫治疗反应增强相关（p=0.0046）。为了进行验证，我们在外部临床队列中进行了体外实验。结果表明，高PSscore组的GSDMD表达水平与低PSscore组相比显著上调（p<0.001）；与低PSscore组相比，高PSscore组的CD3+T细胞和CD3+PD-1+细胞显著增加（p<0.01）。
细胞焦亡调控模式的PSscore是一种可靠的生物标志物，对预测胶质瘤患者的预后、TME和ICB治疗效率具有重要价值。
