近日，比利时鲁汶大学Jean-Christophe Marine等研究人员合作发现，依赖于TCF4的基因调控网络使黑色素瘤对免疫疗法产生抗药性。2024年1月4日出版的《细胞》杂志发表了这项成果。
为了更好地理解免疫检查点阻断疗法（ICB）的内在耐药性，研究人员建立了一个治疗无效黑色素瘤生态系统细胞构成的全面视图，并研究了它在ICB作用下的演变。研究人员利用单细胞空间多组学研究表明，肿瘤微环境促进了复杂的黑色素瘤转录组景观的出现。黑色素瘤细胞具有间质样（MES）状态，这种细胞群已知会对靶向治疗产生抗药性，它们在ICB非应答者的早期治疗活检中明显富集。TCF4是MES特征的核心调控因子，也是黑色素细胞和抗原递呈转录程序的抑制因子，是这一特征的枢纽。
使用溴域抑制剂在基因上或药理学上靶向TCF4，可增加MES细胞的免疫原性和对ICB及靶向治疗的敏感性。研究人员由此发现了一个依赖于TCF4的调控网络，该网络协调多个转录程序，并导致黑色素瘤对靶向治疗和ICB产生耐药性。
附：英文原文
Title: A TCF4-dependent gene regulatory network confers resistance to immunotherapy in melanoma
Author: Joanna Pozniak, Dennis Pedri, Ewout Landeloos, Yannick Van Herck, Asier Antoranz, Lukas Vanwynsberghe, Ada Nowosad, Niccolò Roda, Samira Makhzami, Greet Bervoets, Lucas Ferreira Maciel, Carlos Ariel Pulido-Vicua, Lotte Pollaris, Ruth Seurinck, Fang Zhao, Karine Flem-Karlsen, William Damsky, Limin Chen, Despoina Karagianni, Sonia Cinque, Sam Kint, Katy Vandereyken, Benjamin Rombaut, Thierry Voet, Frank Vernaillen, Wim Annaert, Diether Lambrechts, Veerle Boecxstaens, Yvan Saeys, Joost van den Oord, Francesca Bosisio, Panagiotis Karras, A. Hunter Shain, Marcus Bosenberg, Eleonora Leucci, Annette Paschen, Florian Rambow, Oliver Bechter, Jean-Christophe Marine
Issue&Volume: 2024/01/04
Abstract: To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.
DOI: 10.1016/j.cell.2023.11.037
Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01322-3