Yang Xiao, Wu Yingyi, Chen Xingyu, Qiu Jiayue, Huang Chen
Dr. Nesher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR 999078, China.
Int J Mol Sci. 2024 Mar 6;25(5):3041. doi: 10.3390/ijms25053041.
The prognosis of patients with malignant melanoma has been improved in recent decades due to advancements in immunotherapy. However, a considerable proportion of patients are refractory to treatment, particularly at advanced stages. This underscores the necessity of developing a new strategy to improve it. Alternative polyadenylation (APA), as a marker of crucial posttranscriptional regulation, has emerged as a major new type of epigenetic marker involved in tumorigenesis. However, the potential roles of APA in shaping the tumor microenvironment (TME) are largely unexplored. Herein, we collected two cohorts comprising melanoma patients who received immune checkpoint inhibitor (ICI) immunotherapy to quantify transcriptome-wide discrepancies in APA. We observed a global change in 3'-UTRs between responders and non-responders, which might involve DNA damage response, angiogenesis, PI3K-AKT signaling pathways, etc. Ten putative master APA regulatory factors for those APA events were detected via a network analysis. Notably, we established an immune response-related APA scoring system (IRAPAss), which exhibited a great performance of predicting immunotherapy response in multiple cohorts. Furthermore, we examined the correlation of APA with TME at the single-cell level using four single-cell immune profiles of tumor-infiltrating lymphocytes (TILs), which revealed an overall discrepancy in 3'-UTR length across diverse T cell populations, probably contributing to immunoregulation in melanoma. In conclusion, our study provides a transcriptional landscape of APA implicated in immunoregulation, which might lay the foundation for developing a new strategy for improving immunotherapy response for melanoma patients by targeting APA.
近几十年来，由于免疫疗法的进展，恶性黑色素瘤患者的预后得到了改善。然而，相当一部分患者对治疗无效，尤其是在晚期阶段。这突出了制定新策略以改善预后的必要性。可变聚腺苷酸化（APA）作为关键的转录后调控标记，已成为参与肿瘤发生的一种主要新型表观遗传标记。然而，APA在塑造肿瘤微环境（TME）中的潜在作用在很大程度上尚未得到探索。在此，我们收集了两个队列，其中包括接受免疫检查点抑制剂（ICI）免疫治疗的黑色素瘤患者，以量化全转录组范围内APA的差异。我们观察到应答者和非应答者之间3'-UTR的全局变化，这可能涉及DNA损伤反应、血管生成、PI3K-AKT信号通路等。通过网络分析检测到了这些APA事件的十个假定的主要APA调控因子。值得注意的是，我们建立了一个免疫反应相关的APA评分系统（IRAPAss），该系统在多个队列中表现出对免疫治疗反应的良好预测性能。此外，我们使用肿瘤浸润淋巴细胞（TILs）的四种单细胞免疫图谱在单细胞水平上研究了APA与TME的相关性，结果显示不同T细胞群体的3'-UTR长度存在总体差异，这可能有助于黑色素瘤的免疫调节。总之，我们的研究提供了一个与免疫调节相关的APA转录图谱，这可能为通过靶向APA开发改善黑色素瘤患者免疫治疗反应的新策略奠定基础。
