Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms
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.
Authors
- Santiago Revale (ORCID: https://orcid.org/0000-0001-5219-9582)
- Máire Ní Leathlobhair (ORCID: https://orcid.org/0000-0002-8523-4935)
- Piyush Kumar Sharma (ORCID: https://orcid.org/0000-0002-6247-3503)
- Philip Charlton (ORCID: https://orcid.org/0000-0003-0752-1960)
- Alexander V. Ratushny (ORCID: https://orcid.org/0000-0002-1701-4084)
- Lara R. Heij (ORCID: https://orcid.org/0000-0002-0602-3356)
- Isar Nassiri (ORCID: https://orcid.org/0000-0003-1886-1151)
- Ashwin Jainarayanan (ORCID: https://orcid.org/0000-0003-3523-1477)
- Hubert Slawinski (ORCID: https://orcid.org/0000-0002-8996-8477)
- Rachael Bashford-Rogers (ORCID: https://orcid.org/0000-0002-6838-0711)
- Assaf Magen (ORCID: https://orcid.org/0000-0001-5473-274X)
- Samarth Hegde (ORCID: https://orcid.org/0000-0001-6319-0372)
- Michael Loran Dustin (ORCID: https://orcid.org/0000-0003-4983-6389)
- Maria Wang (ORCID: https://orcid.org/0000-0001-8133-1108)
- Georg Wiltberger (ORCID: https://orcid.org/0000-0003-2384-3847)
- Tim Elliott (ORCID: https://orcid.org/0000-0003-1097-0222)
- Mark R. Middleton (ORCID: https://orcid.org/0000-0003-0167-1685)
- Suzana S. Couto (ORCID: https://orcid.org/0000-0001-6932-5442)
- Laura Spiers (ORCID: https://orcid.org/0000-0001-5639-0499)
- Edward Arbe-Barnes
- Shivan Sivakumar (ORCID: https://orcid.org/0000-0002-5175-2697)
- Miriam Mérad (ORCID: https://orcid.org/0000-0002-4481-7827)
- Bo Sun (ORCID: https://orcid.org/0000-0002-5507-6657)
- Adam E. Frampton (ORCID: https://orcid.org/0000-0002-1392-2755)
- Felicia Anna Tucci (ORCID: https://orcid.org/0000-0001-5813-9708)
- Dimitra Peppa (ORCID: https://orcid.org/0000-0002-9281-5471)
- Ulf P. Neumann (ORCID: https://orcid.org/0000-0002-3831-8917)
- Jonathon Webber
- David J. Reiss (ORCID: https://orcid.org/0000-0001-5392-3034)
- Enas Abu‐Shah (ORCID: https://orcid.org/0000-0001-5033-8171)
- Gerard D. Hoeltzel (ORCID: https://orcid.org/0000-0001-7267-6390)
- Benjamin P. Fairfax (ORCID: https://orcid.org/0000-0001-7413-5002)
- Shihong Wu (ORCID: https://orcid.org/0000-0002-8684-8330)
- Nithishwer Mouroug Anand (ORCID: https://orcid.org/0000-0003-0852-7141)
- Sakina Amin (ORCID: https://orcid.org/0000-0002-5680-8928)
- Thomas Lila
- Pallavur V. Sivakumar
Institutions
- Centre for Human Genetics (GB)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Trinity College Dublin (IE)
- Royal Surrey County Hospital (GB)
- Maastricht University Medical Centre (NL)
- Hammersmith Hospital (GB)
- Nuffield Orthopaedic Centre (GB)
- John Radcliffe Hospital (GB)
- University of Surrey (GB)
- Maastricht University (NL)
- University of Oxford (GB)
- Bristol-Myers Squibb (United States) (US)
- CRUK/MRC Oxford Institute for Radiation Oncology (GB)
- Immune Regulation (United Kingdom) (GB)
- Cancer Research UK Oxford Centre (GB)
- University College London (GB)
- Imperial College London (GB)
- University of Birmingham (GB)
- RWTH Aachen University (DE)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1038/s41467-024-55424-2
- Citations
- 28
- Primary Topic
- Pancreatic and Hepatic Oncology Research
- Type
- article
- Field-Weighted Citation Impact
- 29.27
Funders
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- University of Oxford
- Patrick Berthoud Charitable Trust
- National Institutes of Health
- National Cancer Institute