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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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55424-2 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Shivan Sivakumar |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2e264a4e8501497cb2325e4127512bf4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-2e264a4e8501497cb2325e4127512bf42025-02-09T12:44:58ZengNature PortfolioNature Communications2041-17232025-02-0116112010.1038/s41467-024-55424-2Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanismsShivan Sivakumar0Ashwin Jainarayanan1Edward Arbe-Barnes2Piyush Kumar Sharma3Maire Ni Leathlobhair4Sakina Amin5David J. Reiss6Lara Heij7Samarth Hegde8Assaf Magen9Felicia Tucci10Bo Sun11Shihong Wu12Nithishwer Mouroug Anand13Hubert Slawinski14Santiago Revale15Isar Nassiri16Jonathon Webber17Gerard D. Hoeltzel18Adam E. Frampton19Georg Wiltberger20Ulf Neumann21Philip Charlton22Laura Spiers23Tim Elliott24Maria Wang25Suzana Couto26Thomas Lila27Pallavur V. Sivakumar28Alexander V. Ratushny29Mark R. Middleton30Dimitra Peppa31Benjamin Fairfax32Miriam Merad33Michael L. Dustin34Enas Abu-Shah35Rachael Bashford-Rogers36Department of Oncology, University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, HeadingtonOxford University Clinical Academic Graduate School, John Radcliffe Hospital, University of OxfordDepartment of Oncology, University of OxfordDepartment of Microbiology, Trinity CollegeDepartment of Biochemistry, South Parks Road, University of OxfordBristol-Myers Squibb, SeattleGROW School for Oncology and Developmental Biology, Department of Pathology, Maastricht University Medical CenterPrecision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy PlPrecision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy PlDepartment of Biochemistry, South Parks Road, University of OxfordNuffield Department of Clinical Neurosciences, University of OxfordDepartment of Biochemistry, South Parks Road, University of OxfordDepartment of Biochemistry, South Parks Road, University of OxfordWellcome Centre for Human Genetics, University of OxfordWellcome Centre for Human Genetics, University of OxfordWellcome Centre for Human Genetics, University of OxfordKennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, HeadingtonDepartment of Biochemistry, South Parks Road, University of OxfordMinimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson RoadDepartment of General, Visceral, and Transplantation Surgery, University Hospital of RWTH AachenDepartment of General, Visceral, and Transplantation Surgery, University Hospital of RWTH AachenDepartment of Oncology, University of OxfordDepartment of Oncology, University of OxfordCentre for Immuno-oncology, Nuffield Department of Medicine, University of OxfordBristol-Myers Squibb, SeattleNeomorph, Inc., 5590 Morehouse DrBristol-Myers Squibb, SeattleBristol-Myers Squibb, SeattleBristol-Myers Squibb, SeattleDepartment of Oncology, University of OxfordUCL Institute of Immunity & Transplantation, The Pears Building, Pond StreetDepartment of Oncology, University of OxfordPrecision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy PlKennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, HeadingtonKennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, HeadingtonDepartment of Biochemistry, South Parks Road, University of OxfordAbstract 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.https://doi.org/10.1038/s41467-024-55424-2 |
| spellingShingle | 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 Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms Nature Communications |
| title | Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms |
| title_full | Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms |
| title_fullStr | Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms |
| title_full_unstemmed | Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms |
| title_short | Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms |
| title_sort | distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma pdac exhibit divergent immune cell selection and immunosuppressive mechanisms |
| url | https://doi.org/10.1038/s41467-024-55424-2 |
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