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Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms

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  • Shivan Sivakumar

    (University of Oxford
    Roosevelt Dr, Headington
    Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham)

  • Ashwin Jainarayanan

    (Roosevelt Dr, Headington
    University of Oxford)

  • Edward Arbe-Barnes

    (University of Oxford
    Pond Street)

  • Piyush Kumar Sharma

    (University of Oxford)

  • Maire Ni Leathlobhair

    (Trinity College
    University of Oxford)

  • Sakina Amin

    (University of Oxford)

  • David J. Reiss

    (Bristol-Myers Squibb, Seattle)

  • Lara Heij

    (Maastricht University Medical Center
    University Hospital RWTH Aachen)

  • Samarth Hegde

    (1 Gustave L. Levy Pl)

  • Assaf Magen

    (1 Gustave L. Levy Pl)

  • Felicia Tucci

    (University of Oxford
    Oxford Cancer Centre
    University of Oxford)

  • Bo Sun

    (University of Oxford)

  • Shihong Wu

    (University of Oxford
    Oxford Cancer Centre)

  • Nithishwer Mouroug Anand

    (University of Oxford)

  • Hubert Slawinski

    (University of Oxford)

  • Santiago Revale

    (University of Oxford)

  • Isar Nassiri

    (University of Oxford)

  • Jonathon Webber

    (Roosevelt Dr, Headington)

  • Gerard D. Hoeltzel

    (University of Oxford)

  • Adam E. Frampton

    (Daphne Jackson Road
    Egerton Road
    University of Surrey
    Hammersmith Hospital Campus)

  • Georg Wiltberger

    (University Hospital of RWTH Aachen)

  • Ulf Neumann

    (University Hospital of RWTH Aachen
    Department of Surgery Maastricht University Medical Center (MUMC))

  • Philip Charlton

    (University of Oxford)

  • Laura Spiers

    (University of Oxford)

  • Tim Elliott

    (University of Oxford)

  • Maria Wang

    (Bristol-Myers Squibb, Seattle)

  • Suzana Couto

    (5590 Morehouse Dr)

  • Thomas Lila

    (Bristol-Myers Squibb, Seattle)

  • Pallavur V. Sivakumar

    (Bristol-Myers Squibb, Seattle)

  • Alexander V. Ratushny

    (Bristol-Myers Squibb, Seattle)

  • Mark R. Middleton

    (University of Oxford)

  • Dimitra Peppa

    (Pond Street
    University of Oxford)

  • Benjamin Fairfax

    (University of Oxford)

  • Miriam Merad

    (1 Gustave L. Levy Pl)

  • Michael L. Dustin

    (Roosevelt Dr, Headington
    University of Oxford)

  • Enas Abu-Shah

    (Roosevelt Dr, Headington
    University of Oxford)

  • Rachael Bashford-Rogers

    (University of Oxford
    Oxford Cancer Centre
    University of Oxford)

Abstract

Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Adaptive immune cell-enriched is intrinsically linked with highly distinct B and T cell clonal selection, diversification, and differentiation. Using TCR data, we see the largest clonal expansions in CD8 effector memory, senescent cells, and highly activated regulatory T cells which are induced within the tumour from naïve cells. We identify pathways that potentially lead to a suppressive microenvironment, including investigational targets TIGIT/PVR and SIRPA/CD47. Analysis of patients from the APACT clinical trial shows that myeloid enrichment had a shorter overall survival compared to those with adaptive cell enrichment. Strategies for rationale therapeutic development in this disease include boosting of B cell responses, targeting immunosuppressive macrophages, and specific Treg cell depletion approaches.

Suggested Citation

  • Shivan Sivakumar & Ashwin Jainarayanan & Edward Arbe-Barnes & Piyush Kumar Sharma & Maire Ni Leathlobhair & Sakina Amin & David J. Reiss & Lara Heij & Samarth Hegde & Assaf Magen & Felicia Tucci & Bo , 2025. "Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55424-2
    DOI: 10.1038/s41467-024-55424-2
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    References listed on IDEAS

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    1. Luis A. Rojas & Zachary Sethna & Kevin C. Soares & Cristina Olcese & Nan Pang & Erin Patterson & Jayon Lihm & Nicholas Ceglia & Pablo Guasp & Alexander Chu & Rebecca Yu & Adrienne Kaya Chandra & There, 2023. "Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer," Nature, Nature, vol. 618(7963), pages 144-150, June.
    2. Marta Łuksza & Zachary M. Sethna & Luis A. Rojas & Jayon Lihm & Barbara Bravi & Yuval Elhanati & Kevin Soares & Masataka Amisaki & Anton Dobrin & David Hoyos & Pablo Guasp & Abderezak Zebboudj & Rebec, 2022. "Neoantigen quality predicts immunoediting in survivors of pancreatic cancer," Nature, Nature, vol. 606(7913), pages 389-395, June.
    3. Julienne L. Carstens & Pedro Correa de Sampaio & Dalu Yang & Souptik Barua & Huamin Wang & Arvind Rao & James P. Allison & Valerie S. LeBleu & Raghu Kalluri, 2017. "Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer," Nature Communications, Nature, vol. 8(1), pages 1-13, April.
    4. Ana Raquel Maceiras & Silvia Cristina Paiva Almeida & Encarnita Mariotti-Ferrandiz & Wahiba Chaara & Fadi Jebbawi & Adrien Six & Shohei Hori & David Klatzmann & Jose Faro & Luis Graca, 2017. "T follicular helper and T follicular regulatory cells have different TCR specificity," Nature Communications, Nature, vol. 8(1), pages 1-12, April.
    5. Peter Bailey & David K. Chang & Katia Nones & Amber L. Johns & Ann-Marie Patch & Marie-Claude Gingras & David K. Miller & Angelika N. Christ & Tim J. C. Bruxner & Michael C. Quinn & Craig Nourse & L. , 2016. "Genomic analyses identify molecular subtypes of pancreatic cancer," Nature, Nature, vol. 531(7592), pages 47-52, March.
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