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@ARTICLE{Ahmed:181848,
      author       = {A. Ahmed$^*$ and R. Klotz and S. Köhler and N. Giese and
                      T. Hackert and C. Springfeld and D. Jäger$^*$ and N.
                      Halama$^*$},
      title        = {{I}mmune features of the peritumoral stroma in pancreatic
                      ductal adenocarcinoma.},
      journal      = {Frontiers in immunology},
      volume       = {13},
      issn         = {1664-3224},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {DKFZ-2022-02263},
      pages        = {947407},
      year         = {2022},
      note         = {#EA:D240#LA:D240# / HI-TRON},
      abstract     = {The peritumoral stroma is a hallmark of pancreatic ductal
                      adenocarcinoma (PDA) with implications for disease
                      development, progression and therapy resistance. We
                      systematically investigated immune features of the stroma in
                      PDA patients to identify markers of clinical importance and
                      potential therapeutic targets.Tissue and blood samples of 51
                      PDA patients with clinical and follow-up information were
                      included. Laser Capture Microdissection allowed us to
                      analyze the stromal compartment in particular. Systematic
                      immunohistochemistry, followed by software-based image
                      analysis were conducted. Also, multiplex cytokine analyses
                      (including 50 immune-related molecules) were performed.
                      Functional analyses were performed using patient-derived 3D
                      bioprints. Clinical information was used for survival
                      analyses. Intercompartmental IL9 and IL18 gradients were
                      assessed in matched samples of tumor epithelium, stroma, and
                      serum of patients. Serum levels were compared to an
                      age-matched healthy control group.Stromal IL9 and IL18 are
                      significantly associated with patient survival. While IL9 is
                      a prognostic favorable marker (p=0.041), IL18 associates
                      with poor patient outcomes (p=0.030). IL9 correlates with an
                      anti-tumoral cytokine network which connects regulation of T
                      helper (Th) 9, Th1 and Th17 cells (all: p<0.05 and r>0.5).
                      IL18 correlates with a Th1-type cytokine phenotype and
                      stromal CXCL12 expression (all: p<0.05 and r>0.5). Further,
                      IL18 associates with a higher level of exhausted T cells.
                      Inhibition of IL18 results in diminished Th1- and Th2-type
                      cytokines. Patients with high stromal IL9 expression have a
                      tumor-to-stroma IL9 gradient directed towards the stroma
                      (p=0.019). Low IL18 expression associates with a
                      tumor-to-stroma IL18 gradient away from the stroma
                      (p=0.007). PDA patients showed higher serum levels of IL9
                      than healthy controls while serum IL18 levels were
                      significantly lower than in healthy individuals. The stromal
                      immune cell composition is distinct from the tumor
                      epithelium. Stromal density of FoxP3+ regulatory T cells
                      showed a tendency towards improved patient survival
                      (p=0.071).An unexpected high expression of the cytokines IL9
                      and IL18 at different ends is of significance in the stroma
                      of PDA and relates to opposing patient outcomes.
                      Sub-compartmental cytokine analyses highlight the importance
                      of a differentiated gradient assessment. The findings
                      suggest stromal IL9 and/or IL18 as markers for patient
                      stratification and as potential therapeutic targets. Future
                      steps include investigating e. g. the role of local
                      microbiota as both cytokines are also regulated by microbial
                      compositions.},
      keywords     = {Carcinoma, Pancreatic Ductal: pathology / Cytokines /
                      Forkhead Transcription Factors / Humans / Interleukin-18 /
                      Interleukin-9 / Pancreatic Neoplasms: pathology / IL18
                      (Other) / IL9 (Other) / pancreatic cancer (Other) / stroma
                      (Other) / stromal immunology (Other) / Cytokines (NLM
                      Chemicals) / Forkhead Transcription Factors (NLM Chemicals)
                      / Interleukin-18 (NLM Chemicals) / Interleukin-9 (NLM
                      Chemicals)},
      cin          = {D240 / D120},
      ddc          = {610},
      cid          = {I:(DE-He78)D240-20160331 / I:(DE-He78)D120-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36131941},
      pmc          = {pmc:PMC9483939},
      doi          = {10.3389/fimmu.2022.947407},
      url          = {https://inrepo02.dkfz.de/record/181848},
}