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 () and Rachael Bashford-Rogers ()
Additional contact information
Shivan Sivakumar: University of Oxford
Ashwin Jainarayanan: Roosevelt Dr, Headington
Edward Arbe-Barnes: University of Oxford
Piyush Kumar Sharma: University of Oxford
Maire Ni Leathlobhair: Trinity College
Sakina Amin: University of Oxford
David J. Reiss: Bristol-Myers Squibb, Seattle
Lara Heij: Maastricht University Medical Center
Samarth Hegde: 1 Gustave L. Levy Pl
Assaf Magen: 1 Gustave L. Levy Pl
Felicia Tucci: University of Oxford
Bo Sun: University of Oxford
Shihong Wu: University of Oxford
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
Georg Wiltberger: University Hospital of RWTH Aachen
Ulf Neumann: University Hospital of RWTH Aachen
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
Benjamin Fairfax: University of Oxford
Miriam Merad: 1 Gustave L. Levy Pl
Michael L. Dustin: Roosevelt Dr, Headington
Enas Abu-Shah: Roosevelt Dr, Headington
Rachael Bashford-Rogers: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55424-2

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