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

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

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-e...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-55424-2
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Summary: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.
ISSN:2041-1723

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