Dobosz Paula, Stempor Przemysław A, Roszik Jason, Herman Amir, Layani Adi, Berger Raanan, Avni Dror, Sidi Yechezkel, Leibowitz-Amit Raya
Oncology Institute and Cancer Research Centre, Sheba Medical Centre Hospital, Tel Hashomer, Ramat Gan, Israel.
School of Life Sciences, Gurdon Institute, Department of Genetics, Tennis Court Rd, Cambridge, UK; The Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Tennis Court Rd, Cambridge, UK; Department of Genetics, University of Cambridge, Downing Street, Cambridge, UK.
Transl Oncol. 2020 Feb;13(2):193-200. doi: 10.1016/j.tranon.2019.10.018. Epub 2019 Dec 20.
Immune checkpoint inhibitors have revolutionized cancer therapy, but not all cancers respond to the currently available drugs, and even within cancers considered responsive to such modality, response rates range between 15 and 40%, depending on the cancer type, the line of treatment, and yet unknown clinical/molecular factors. Coordinated expression of checkpoint proteins was shown to occur on T cells, probably allowing fine-tuning of the signal transmitted to the cell. We performed a bioinformatic analysis of the expression of putative checkpoint mRNAs at the cancer side of the immunological synapse from the bladder cancer tumorgenome atlas (TCGA) database. Fifteen mRNAs, corresponding to both coinhibitory and costimulatory checkpoints, were shown to be expressed above a designated threshold. Of these, seven mRNAs were found to be coexpressed: CD277, PD-1L, CD48, CD86, galectin-9, TNFRSF14 (HVEM), and CD40. The expression of 2 of these mRNAs-BTN3A1 (CD277) and TNFRSF14 (HVEM)-was positively correlated with overall survival in the TCGA database. All these seven mRNA share putative binding sites of a few transcription factors (TFs). Of these, the expression of the TF BACH-2 was positively correlated with the expression of checkpoint mRNAs from the network. This suggests a joint transcriptional regulation on the expression of checkpoint mRNAs at the bladder tumor side of the immunological synapse.
免疫检查点抑制剂彻底改变了癌症治疗方式，但并非所有癌症都对目前可用的药物有反应，即使在被认为对这种治疗方式有反应的癌症中，根据癌症类型、治疗线以及尚不清楚的临床/分子因素，反应率在15%至40%之间。已证明检查点蛋白的协调表达发生在T细胞上，这可能允许对传递到细胞的信号进行微调。我们对来自膀胱癌肿瘤基因组图谱（TCGA）数据库的免疫突触肿瘤侧推定检查点mRNA的表达进行了生物信息学分析。有15种mRNA，对应共抑制和共刺激检查点，显示其表达高于指定阈值。其中，发现有7种mRNA共表达：CD277、PD-1L、CD48、CD86、半乳糖凝集素-9、TNFRSF14（HVEM）和CD40。在TCGA数据库中，这些mRNA中的2种——BTN3A1（CD277）和TNFRSF14（HVEM）——的表达与总生存期呈正相关。所有这7种mRNA都共享一些转录因子（TF）的推定结合位点。其中，TF BACH-2的表达与来自该网络的检查点mRNA的表达呈正相关。这表明在免疫突触的膀胱肿瘤侧对检查点mRNA的表达存在联合转录调控。
