Spatial tumor immune heterogeneity facilitates subtype co-existence and therapy response in pancreatic cancer

Lukas Klein, Mengyu Tu, Niklas Krebs, Laura Urbach, Daniela Grimm, Muhammad Umair Latif, Frederike Penz, Anna Blandau, Xueyan Wu, Rebecca Diya Samuel, Stefan Küffer, Florian Wegwitz, Nathan Chan, Kazeera Aliar, Foram Vyas, Uday Kishore, Elisabeth Hessmann, Andreas Trumpp, Elisa Espinet, Argyris Papantonis, Rama Khokha, Volker Ellenrieder, Barbara T. Grünwald and Shiv K. Singh ()
Additional contact information
Lukas Klein: University Medical Center Göttingen
Mengyu Tu: University Medical Center Göttingen
Niklas Krebs: West German Cancer Center, University Hospital Essen
Laura Urbach: University Medical Center Göttingen
Daniela Grimm: University Medical Center Göttingen
Muhammad Umair Latif: University Medical Center Göttingen
Frederike Penz: University Medical Center Göttingen
Anna Blandau: University Medical Center Göttingen
Xueyan Wu: University Medical Center Göttingen
Rebecca Diya Samuel: University Medical Center Göttingen
Stefan Küffer: University Medical Center Göttingen
Florian Wegwitz: University Medical Center Göttingen
Nathan Chan: University Health Network
Kazeera Aliar: University Health Network
Foram Vyas: University Health Network
Uday Kishore: United Arab Emirates University
Elisabeth Hessmann: University Medical Center Göttingen
Andreas Trumpp: DKFZ
Elisa Espinet: DKFZ
Argyris Papantonis: University Medical Center Göttingen
Rama Khokha: University Health Network
Volker Ellenrieder: University Medical Center Göttingen
Barbara T. Grünwald: University Health Network
Shiv K. Singh: University Medical Center Göttingen

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-024-55330-7

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