Fang Xue-Liang, Li Qing-Jie, Wang Li, Shi Yu-Xuan, Hu Li-Ya, Zhao Xuan-Yu, Lv Wei, Yu Hong-Meng
Department of Otolaryngology, Research Units of New Technologies of Endoscopic Surgery in Skull Base Tumor (2018RU003), Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100000, China.
ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
Clin Transl Oncol. 2024 Dec 31. doi: 10.1007/s12094-024-03829-2.
Despite its crucial role in immune surveillance and cell survival of tumors, the significance of MHC antigen processing and presentation machinery (APM) is still not fully understood in head and neck squamous cell carcinoma (HNSCC). We sought to develop an APM gene score (APMGS) to predict prognosis and reveal the molecular and immune traits of the APMGS-defined subgroups in HNSCC.
Based on the APM-related genes acquired from 6 databases, 117 combined machine learning algorithms were applied to develop APMGS with The Cancer Genome Atlas (TCGA)-HNSCC database and validated with the Gene Expression Omnibus (GEO) dataset. Comprehensive analysis was performed to investigate the molecular and immune features of APMGS subgroups.
The APMGS constructed by StepCox [both] + Ridge method achieved the highest C-index and area under curve (AUC) at 3 years and were thus adopted as the final model. Low-APMGS patients exhibited superior overall survival compared with high-APMGS patients in both TCGA and GEO cohorts. Subsequent analysis confirmed that a low APMGS was associated with immune response-related pathways; low TP53 mutation rate and low tumor mutation burden (TMB); a less aggressive phenotype; high infiltration of activated CD4 memory T cells, CD8 T cells, follicular helper T cells, and Tregs; active immunity; and higher sensitivity to chemotherapeutic and targeted agents. In contrast, a high APMGS linked to proteasome and protein export pathways; high TP53 mutation rate and high TMB; a more aggressive phenotype; high infiltration of M0 macrophages and eosinophils; suppressed immunity; and lower sensitivity to chemotherapeutic and targeted agents.
Our findings suggest that APMGS has potential to predict the prognosis, and molecular and immune characteristics of HNSCC, and may also serve as an indicator for immunotherapy benefit.
尽管MHC抗原加工和呈递机制（APM）在肿瘤的免疫监视和细胞存活中起关键作用，但其在头颈部鳞状细胞癌（HNSCC）中的重要性仍未完全明确。我们试图开发一种APM基因评分（APMGS）来预测预后，并揭示HNSCC中APMGS定义亚组的分子和免疫特征。
基于从6个数据库获取的与APM相关的基因，应用117种组合机器学习算法，利用癌症基因组图谱（TCGA）-HNSCC数据库开发APMGS，并使用基因表达综合数据库（GEO）数据集进行验证。进行综合分析以研究APMGS亚组的分子和免疫特征。
采用StepCox [两者] + 岭回归方法构建的APMGS在3年时达到最高的C指数和曲线下面积（AUC），因此被用作最终模型。在TCGA和GEO队列中，低APMGS患者的总生存期均优于高APMGS患者。随后的分析证实，低APMGS与免疫反应相关途径、低TP53突变率和低肿瘤突变负荷（TMB）、侵袭性较小的表型、活化的CD4记忆T细胞、CD8 T细胞、滤泡辅助性T细胞和调节性T细胞的高浸润、主动免疫以及对化疗和靶向药物的更高敏感性相关。相反，高APMGS与蛋白酶体和蛋白质输出途径、高TP53突变率和高TMB、侵袭性更强的表型、M0巨噬细胞和嗜酸性粒细胞的高浸润、免疫抑制以及对化疗和靶向药物的较低敏感性相关。
我们的研究结果表明，APMGS有潜力预测HNSCC的预后、分子和免疫特征，也可能作为免疫治疗获益的指标。
