Budhwani Megha, Turrell Gavin, Yu Meihua, Frazer Ian H, Mehdi Ahmed M, Chandra Janin
The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.
Front Mol Biosci. 2021 Mar 23;8:622643. doi: 10.3389/fmolb.2021.622643. eCollection 2021.
Limited immunotherapy options are approved for the treatment of cervical cancer and only 10-25% of patients respond effectively to checkpoint inhibition monotherapy. To aid the development of novel therapeutic immune targets, we aimed to explore survival-associated immune biomarkers and co-expressed immune networks in cervical cancer. Using The Cancer Genome Atlas (TCGA) Cervical Squamous Cell Carcinoma (CESC) data ( = 304), we performed weighted gene co-expression network analysis (WGCNA), and determined which co-expressed immune-related genes and networks are associated with survival probability in CESC patients under conventional therapy. A "Pan-Immune Score" and "Immune Suppression Score" was generated based on expression of survival-associated co-expressed immune networks and immune suppressive genes, which were subsequently tested for association with survival probablity using the TCGA Head Neck Squamous Cell Carcinoma (HNSCC) data ( = 528), representing a second SCC cancer type. In CESC, WGCNA identified a co-expression module enriched in immune response related genes, including 462 genes where high expression was associated with increased survival probability, and enriched for genes associated with T cell receptor, cytokine and chemokine signaling. However, a high level of expression of 43 of the genes in this module was associated with decreased survival probability but were not enriched in particular pathways. Separately, we identified 20 genes associated with immune suppression including inhibitory immune checkpoint and regulatory T cell-related genes, where high expression was associated with increased survival probability. Expression of these 20 immune suppressive genes (represented as "Immune Suppression Score") was highly correlated with expression of overall survival-associated immune genes (represented as "Pan-Immune Score"). However, high expression of seven immune suppression genes, including TWEAK-R, CD73, IL1 family and TGFb family genes, was significantly associated with decreased survival probability. Both scores also significantly associated with survival probability in HNSCC, and correlated with the previously established "Immunophenoscore." CESC and HNSCC tumors expressing genes predictive of T cell infiltrates (hot tumors) have a better prognosis, despite simultaneous expression of many immune inhibitory genes, than tumors lacking expression of genes associated with T cell infiltrates (cold tumors) whether or not these tumor express immune inhibitory genes.
目前仅有有限的免疫疗法被批准用于治疗宫颈癌，只有10%-25%的患者对检查点抑制单一疗法有有效反应。为了助力新型治疗性免疫靶点的开发，我们旨在探索宫颈癌中与生存相关的免疫生物标志物和共表达免疫网络。利用癌症基因组图谱（TCGA）的宫颈鳞状细胞癌（CESC）数据（n = 304），我们进行了加权基因共表达网络分析（WGCNA），并确定了哪些共表达的免疫相关基因和网络与接受传统治疗的CESC患者的生存概率相关。基于与生存相关的共表达免疫网络和免疫抑制基因的表达生成了“泛免疫评分”和“免疫抑制评分”，随后使用TCGA头颈鳞状细胞癌（HNSCC）数据（n = 528）对其与生存概率的相关性进行了检验，HNSCC代表另一种鳞状细胞癌类型。在CESC中，WGCNA识别出一个富含免疫反应相关基因的共表达模块，包括462个高表达与生存概率增加相关的基因，并且富含与T细胞受体、细胞因子和趋化因子信号传导相关的基因。然而，该模块中43个基因的高表达与生存概率降低相关，但未在特定途径中富集。另外，我们鉴定出20个与免疫抑制相关的基因，包括抑制性免疫检查点和调节性T细胞相关基因，其高表达与生存概率增加相关。这20个免疫抑制基因的表达（表示为“免疫抑制评分”）与总体生存相关免疫基因的表达（表示为“泛免疫评分”）高度相关。然而，包括TWEAK-R、CD73、IL1家族和TGFb家族基因在内的7个免疫抑制基因的高表达与生存概率降低显著相关。这两个评分在HNSCC中也与生存概率显著相关，并且与先前建立的“免疫表型评分”相关。表达预测T细胞浸润的基因（热肿瘤）的CESC和HNSCC肿瘤，尽管同时表达许多免疫抑制基因，但其预后比缺乏与T细胞浸润相关基因表达的肿瘤（冷肿瘤）更好，无论这些肿瘤是否表达免疫抑制基因。
