Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium; Laboratory for Membrane Trafficking, Center for Brain and Disease Research, VIB, Leuven, Belgium.
Cell. 2024 Jan 4;187(1):166-183.e25. doi: 10.1016/j.cell.2023.11.037.
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.
为了更好地理解免疫检查点阻断（ICB）的内在耐药性，我们建立了一个全面的治疗初治黑色素瘤生态系统的细胞结构视图，并研究了其在 ICB 下的进化。使用单细胞、空间多组学，我们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。在对 ICB 无反应者的早期治疗活检中，具有间充质样（MES）状态的黑色素瘤细胞明显富集，该群体已知对靶向治疗有抗性。TCF4 是该景观的枢纽，它是 MES 特征的主要调节剂，也是黑素细胞和抗原呈递转录程序的抑制剂。通过使用溴结构域抑制剂在遗传或药理学上靶向 TCF4，增加了 MES 细胞对 ICB 和靶向治疗的免疫原性和敏感性。因此，我们揭示了一个 TCF4 依赖性调节网络，该网络协调多个转录程序，并有助于黑色素瘤对靶向治疗和 ICB 的耐药性。
