Zhang Yueming, Lin Anqi, Li Yonghe, Ding Weimin, Meng Hui, Luo Peng, Zhang Jian
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Otolaryngology-Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Front Cell Dev Biol. 2020 Dec 9;8:608969. doi: 10.3389/fcell.2020.608969. eCollection 2020.
The immunosuppressive tumor microenvironment plays an essential role in the treatment of head and neck squamous cell carcinoma (HNSC). Compared to traditional chemoradiotherapy, immune checkpoint inhibitors (ICIs) have become increasingly important in HNSC therapy. Prior studies linked the efficacy of ICIs to PD-L1, microsatellite instability (MSI), HPV infection, tumor mutation burden (TMB), and tumor lymphocyte infiltration in patients with HNSC, but further verification is needed. Additional predictors are needed to recognize HNSC patients with a good response to ICIs. We collected the clinical information and mutation data of HNSC patients from Memorial Sloan Kettering Cancer Center (MSKCC) and The Cancer Genome Atlas (TCGA) databases to generate two clinical cohorts. The MSKCC cohort was used to recognize predictors related to the efficacy of ICIs, and the TCGA cohort was used to further examine the immune microenvironment features and signaling pathways that are significantly enriched in the subgroups of predictors. Multivariate Cox regression analysis indicated that age (HR = 0.50, = 0.014) and ARID1A (HR = 0.13, = 0.048), PIK3CA (HR = 0.45, = 0.021), and TP53 (HR = 1.82, = 0.035) mutations were potential predictors for ICI efficacy in HNSC patients. Age > 65 years and ARID1A or PIK3CA mutations correlated with good overall survival (OS). TP53 mutant-type (MT) patients experienced a worse prognosis than TP53 wild-type (WT) patients. The subgroups associated with a good prognosis (age > 65 years, ARID1A-MT, and PIK3CA-MT) universally had a high TMB and increased expression of immune checkpoint molecules. Although TP53-MT was associated with a high TMB, the expression of most immune checkpoint molecules and immune-related genes was lower in TP53-MT patients than TP53-WT patients, which may reflect low immunogenicity. Pathways related to the immunosuppressive tumor microenvironment were mostly enriched in the subgroups associated with a poor prognosis (age ≤ 65 years, low TMB, ARID1A-WT, PIK3CA-WT, and TP53-MT). In conclusion, the factors age > 65 years, PIK3CA-MT, and ARID1A-MT predicted favorable efficacy for ICI treatment in HNSC patients, and TP53 mutation was a negative predictor.
免疫抑制性肿瘤微环境在头颈部鳞状细胞癌（HNSC）的治疗中起着至关重要的作用。与传统的放化疗相比，免疫检查点抑制剂（ICIs）在HNSC治疗中变得越来越重要。先前的研究将ICIs的疗效与HNSC患者的程序性死亡受体配体1（PD-L1）、微卫星不稳定性（MSI）、人乳头瘤病毒（HPV）感染、肿瘤突变负荷（TMB）以及肿瘤淋巴细胞浸润联系起来，但仍需要进一步验证。需要更多的预测指标来识别对ICIs反应良好的HNSC患者。我们从纪念斯隆凯特琳癌症中心（MSKCC）和癌症基因组图谱（TCGA）数据库收集了HNSC患者的临床信息和突变数据，以生成两个临床队列。MSKCC队列用于识别与ICIs疗效相关的预测指标，TCGA队列用于进一步研究在预测指标亚组中显著富集的免疫微环境特征和信号通路。多变量Cox回归分析表明，年龄（风险比[HR]=0.50，P=0.014）以及AT丰富结合域1A（ARID1A，HR=0.13，P=0.048）、磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α（PIK3CA，HR=0.45，P=0.021）和肿瘤蛋白p53（TP53，HR=1.82，P=0.035）的突变是HNSC患者ICI疗效的潜在预测指标。年龄>65岁以及ARID1A或PIK3CA突变与良好的总生存期（OS）相关。TP53突变型（MT）患者的预后比TP53野生型（WT）患者更差。与良好预后相关的亚组（年龄>65岁、ARID1A-MT和PIK3CA-MT）普遍具有高TMB和免疫检查点分子表达增加。虽然TP53-MT与高TMB相关，但TP53-MT患者中大多数免疫检查点分子和免疫相关基因的表达低于TP53-WT患者，这可能反映了低免疫原性。与免疫抑制性肿瘤微环境相关的信号通路大多在与不良预后相关的亚组（年龄≤65岁、低TMB、ARID1A-WT、PIK3CA-WT和TP53-MT）中富集。总之，年龄>65岁、PIK3CA-MT和ARID1A-MT这些因素预测了ICIs治疗HNSC患者的良好疗效，而TP53突变是一个负面预测指标。
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