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

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 Sun; Shihong Wu; Nithishwer Mouroug Anand; Hubert Slawinski; Santiago Revale; Isar Nassiri; Jonathon Webber; Gerard D Hoeltzel; Adam E Frampton; Georg Wiltberger; Ulf Neumann; Philip Charlton; Laura Spiers; Tim Elliott; Maria Wang; Suzana Couto; Thomas Lila; Pallavur V Sivakumar; Alexander V Ratushny; Mark R Middleton; Dimitra Peppa; Benjamin Fairfax; Miriam Merad; Michael L Dustin; Enas Abu-Shah; Rachael Bashford-Rogers

doi:10.1038/s41467-024-55424-2

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

Nat Commun. 2025 Feb 6;16(1):1397. doi: 10.1038/s41467-024-55424-2.

Authors

Shivan Sivakumar^#^{1

2

3}, Ashwin Jainarayanan^#^{4

5}, Edward Arbe-Barnes^#^{6

7}, Piyush Kumar Sharma^#⁸, Maire Ni Leathlobhair^#^{9

10}, Sakina Amin^#¹¹, David J Reiss^#¹², Lara Heij^{13

14}, Samarth Hegde¹⁵, Assaf Magen¹⁵, Felicia Tucci^{11

16

17}, Bo Sun¹⁸, Shihong Wu^{11

16}, Nithishwer Mouroug Anand¹¹, Hubert Slawinski¹⁷, Santiago Revale¹⁷, Isar Nassiri¹⁷, Jonathon Webber⁴, Gerard D Hoeltzel¹¹, Adam E Frampton^{19

20

21

22}, Georg Wiltberger²³, Ulf Neumann^{23

24}, Philip Charlton⁸, Laura Spiers⁸, Tim Elliott²⁵, Maria Wang¹², Suzana Couto²⁶, Thomas Lila¹², Pallavur V Sivakumar¹², Alexander V Ratushny¹², Mark R Middleton⁸, Dimitra Peppa^{7

27}, Benjamin Fairfax⁸, Miriam Merad¹⁵, Michael L Dustin^{4

28}, Enas Abu-Shah^{29

30}, Rachael Bashford-Rogers^{31

32

33}

Affiliations

¹ Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK. s.sivakumar@bham.ac.uk.
² Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, Headington, Oxford, OX3 7FY, UK. s.sivakumar@bham.ac.uk.
³ Department of Immunology and Immunotherapy, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham, Birmingham, B15 2TT, UK. s.sivakumar@bham.ac.uk.
⁴ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, Headington, Oxford, OX3 7FY, UK.
⁵ Institute of Developmental and Regenerative Medicine (IDRM), Old Road Campus, Old Rd, Roosevelt Dr, Headington, University of Oxford, Oxford, OX3 7TY, UK.
⁶ Oxford University Clinical Academic Graduate School, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
⁷ UCL Institute of Immunity & Transplantation, The Pears Building, Pond Street, London, NW3 2PP, UK.
⁸ Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK.
⁹ Department of Microbiology, Trinity College, Dublin, Ireland.
¹⁰ Oxford Big Data Institute, Old Road Campus, University of Oxford, Oxford, OX3 7LF, UK.
¹¹ Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK.
¹² Bristol-Myers Squibb, Seattle, Seattle, WA, USA.
¹³ GROW School for Oncology and Developmental Biology, Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.
¹⁴ Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.
¹⁵ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY, 10029, USA.
¹⁶ Oxford Cancer Centre, Oxford, UK.
¹⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
¹⁸ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 7LD, UK.
¹⁹ Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford, GU2 7WG, UK.
²⁰ Department of Hepato-Pancreato-Biliary (HPB) Surgery, Royal Surrey County Hospital, Egerton Road, Guildford, GU2 7XX, UK.
²¹ Targeted Cancer Therapy Unit, Department of Clinical and Experimental Medicine, Faculty of Health and Medical Science, University of Surrey, Guildford, GU2 7WG, UK.
²² Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
²³ Department of General, Visceral, and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany.
²⁴ Department of Surgery Maastricht University Medical Center (MUMC), Maastricht, The Netherlands.
²⁵ Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
²⁶ Neomorph, Inc., 5590 Morehouse Dr, San Diego, CA, USA.
²⁷ Nuffield Department of Medicine, Old Road Campus, University of Oxford, Oxford, OX3 7BN, UK.
²⁸ Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
²⁹ Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, Headington, Oxford, OX3 7FY, UK. enas.abushah@path.ox.ac.uk.
³⁰ Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, OX1 3RE, UK. enas.abushah@path.ox.ac.uk.
³¹ Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK. rachael.bashford-rogers@bioch.ox.ac.uk.
³² Oxford Cancer Centre, Oxford, UK. rachael.bashford-rogers@bioch.ox.ac.uk.
³³ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK. rachael.bashford-rogers@bioch.ox.ac.uk.

^# Contributed equally.

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.

MeSH terms

B-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / immunology
Carcinoma, Pancreatic Ductal* / immunology
Carcinoma, Pancreatic Ductal* / mortality
Carcinoma, Pancreatic Ductal* / pathology
Female
Humans
Lymphocytes, Tumor-Infiltrating* / immunology
Macrophages / immunology
Male
Middle Aged
Pancreatic Neoplasms* / immunology
Pancreatic Neoplasms* / mortality
Pancreatic Neoplasms* / pathology
Single-Cell Analysis
T-Lymphocytes, Regulatory / immunology
Tumor Microenvironment / immunology

Abstract

MeSH terms

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