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<p>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<sup>+</sup> macrophages, which associates with a reactive phenotype and reduced CD8<sup>+</sup> T cell infiltration in patients. Consequently, combined preclinical anti-TNF-α immunotherapy and chemotherapy reduces macrophages and promotes CD3<sup>+</sup>/CD8<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月6日

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  • 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,
  • Shiv K. Singh

摘要

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.