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  • Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer

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Pancreas
Original research
Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer
  1. Eva Karamitopoulou1,
  2. Anna Silvia Wenning2,
  3. Animesh Acharjee3,
  4. Inti Zlobec1,
  5. Pauline Aeschbacher2,
  6. Aurel Perren1,
  7. Beat Gloor2
  1. 1 Institute for Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
  2. 2 Department of Visceral Surgery, Insel University Hospital, University of Bern, Bern, Switzerland
  3. 3 University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
  1. Correspondence to Dr Eva Karamitopoulou, Institute for Tissue Medicine and Pathology, University of Bern, Bern 3012, Switzerland; eva.diamantis{at}unibe.ch

Abstract

Objective Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence.

Design PDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK)+CD45− (tumour cells); CD45+PanCK- (leucocytes) and PanCK-CD45- (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel.

Results No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin+ fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP+ fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis.

Conclusions Our findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.

  • pancreatic cancer
  • cancer immunobiology
  • immune response
  • immunohistopathology

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/gutjnl-2022-329371

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • Twitter @DrAnimeshAchar1

    • AP and BG contributed equally.

    • Contributors Conception and design: EK, BG. Development of methodology: EK. Acquisition of data: ASW, PA. Analysis and interpretation of data: EK, AP, AA, IZ. Writing, review and/or revision of the manuscript: EK, BG, ASW, PA, AA, IZ, AP. Administrative, technical or material support: PA. Study supervision: EK, BG, AP. Guarantor: EK.

    • Funding This work was supported in part by the Foundation for Clinical-Experimental TumorResearch (to EK) and Insular Foundation (to BG).

    • Disclaimer The funders had no involvement in the study design; in the collection, analysis and interpretation of the data; in the writing of the report and in the decision to submit the paper for publication.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the 'Methods' section for further details.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.