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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/220472
Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response in pancreatic cancer
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Pancreatic ductal adenocarcinoma (PDAC) displays a high degree of spatial subtype heterogeneity and co-existence, linked to a diverse microenvironment and worse clinical outcome. However, the underlying mechanisms remain unclear. Here, by combining preclinical models, multi-center clinical, transcriptomic, proteomic, and patient bioimaging data, we identify an interplay between neoplastic intrinsic AP1 transcription factor dichotomy and extrinsic macrophages driving subtype co-existence and an immunosuppressive microenvironment. ATAC-, ChIP-, and RNA-seq analyses reveal that JUNB/AP1- and HDAC-mediated epigenetic programs repress pro-inflammatory signatures in tumor cells, antagonizing cJUN/AP1 signaling, favoring a therapy-responsive classical neoplastic state. This dichotomous regulation is amplified via regional TNF-α+ macrophages, which associates with a reactive phenotype and reduced CD8+ T cell infiltration in patients. Consequently, combined preclinical anti-TNF-α immunotherapy and chemotherapy reduces macrophages and promotes CD3+/CD8+ T cell infiltration in basal-like PDAC, improving survival. Hence, tumor cell-intrinsic epigenetic programs, together with extrinsic microenvironmental cues, facilitate intratumoral subtype heterogeneity and disease progression.
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KLEIN, Lukas, TU, Mengyu, KREBS, Niklas, URBACH, Laura, GRIMM, Daniela, LATIF, Muhammad umair, PENZ, Frederike, BLANDAU, Anna, WU, Xueyan, SAMUEL, Rebecca diya, KÜFFER, Stefan, WEGWITZ, Florian, CHAN, Nathan, ALIAR, Kazeera, VYAS, Foram, KISHORE, Uday, HESSMANN, Elisabeth, TRUMPP, Andreas, ESPINET, Elisa, PAPANTONIS, Argyris, KHOKHA, Rama, ELLENRIEDER, Volker, GRÜNWALD, Barbara t., SINGH, Shiv k.. Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response in pancreatic cancer. _Nature Communications_. 2025. Vol. 16, núm. 1. [consulta: 26 de febrer de 2026]. ISSN: 2041-1723. [Disponible a: https://hdl.handle.net/2445/220472]