Single-cell immune multi-omics and repertoire analyses in pancreatic ductal adenocarcinoma reveal differential immunosuppressive mechanisms within different tumour microenvironments

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Understanding the multiple mechanisms by which the tumour evades immune control, and how these mechanisms may be disrupted is critical to developing targeted immunotherapies. Previous studies have shown that higher lymphocyte infiltration is associated with better survival, and here we investigated what mediates these differences. We performed a comprehensive analysis of PDAC-associated immune cells using single cell multi-omics coupled with re-analysis of public PDAC scRNA-seq datasets. We introduce novel single-cell and repertoire analyses that have uncoupled diverse roles and contributions of various immune cell populations within different tumour microenvironments (TMEs). They revealed clear distinctions in the clonal characteristics among different patient groups, provided valuable insights into the mechanisms of immune cell migration and tissue adaptation underlying these disparities. These results point to differential CD4 polarisation of intra-tumoural T cells, differential B cell differentiation, GC reactions, antigen presentation pathways, and distinct cell-cell communication between the myeloid-enriched and adaptive-enriched groups. Overall, we identified two major distinct themes for future immune intervention within PDAC patients between those with higher adaptive versus myeloid immune cell infiltration.

Authors 31

1. Shivan Sivakumar

   University of Oxford

   Affiliation as printed

   Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK;

   Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK

2. Ashwin Jainarayanan

   University of Oxford · Kennedy Institute of Rheumatology

   Affiliation as printed

   Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, Headington, Oxford OX3 7FY, UK;

   Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, Headington, Oxford OX3 7FY, UK

3. Edward H. Arbe-Barnes

   University of Oxford · John Radcliffe Hospital

   Affiliation as printed

   Oxford University Clinical Academic Graduate School, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK;

   Oxford University Clinical Academic Graduate School, John Radcliffe Hospital, University of Oxford, Oxford, OX 9DU, UK

4. Piyush Kumar Sharma

   University of Oxford

   Affiliation as printed

   Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK;

   Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK

5. Máire Ní Leathlobhair

   Trinity College Dublin

   Affiliation as printed

   Department of Microbiology, Trinity College, Dublin, Ireland;

   Department of Microbiology, Trinity College, Dublin, Ireland

6. Sakina Amin

   University of Oxford

   Affiliation as printed

   Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK;

   Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK

7. Lara Rosaline Heij

   Maastricht University · Maastricht University Medical Centre

   Affiliation as printed

   GROW School for Oncology and Developmental Biology, Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands.;

   GROW School for Oncology and Developmental Biology, Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands

8. Samarth Hegde

   Icahn School of Medicine at Mount Sinai

   Affiliation as printed

   Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, United States;

   Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, United States

9. Assaf Magen

   Icahn School of Medicine at Mount Sinai

   Affiliation as printed

   Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, United States;

   Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, United States

10. Felicia Anna Tucci

    University of Oxford

    Affiliation as printed

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK;

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK

11. Bo Sun

    University of Oxford

    Affiliation as printed

    Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 7LD, UK;

    Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford OX3 7LD, UK

12. Shihong Wu

    University of Oxford

    Affiliation as printed

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK;

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK

13. Nithishwer Mouroug Anand

    University of Oxford

    Affiliation as printed

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK;

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK

14. Hubert Slawinski

    University of Oxford · Centre for Human Genetics

    Affiliation as printed

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK;

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

15. Santiago Revale

    University of Oxford · Centre for Human Genetics

    Affiliation as printed

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK;

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

16. Isar Nassiri

    University of Oxford · Centre for Human Genetics

    Affiliation as printed

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK;

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

17. Adam Enver Frampton

    University of Surrey

    Affiliation as printed

    Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK;

    Minimal Access Therapy Training Unit (MATTU), Leggett Building, University of Surrey, Daphne Jackson Road, Guildford GU2 7WG, UK

18. Georg J. Wiltberger Aachen Department of General, Visceral and Transplantation Surgery

    RWTH Aachen University · Universitätsklinikum Aachen

    Affiliation as printed

    Department of General, Visceral, and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany;

    Department of General, Visceral, and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany

19. Ulf P. Neumann Aachen Department of General, Visceral and Transplantation Surgery

    RWTH Aachen University · Universitätsklinikum Aachen · Maastricht University · Maastricht University Medical Centre

    Affiliation as printed

    Department of General, Visceral, and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany; Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands;

    Department of General, Visceral, and Transplantation Surgery, University Hospital of RWTH Aachen, Aachen, Germany

    Department of Surgery, Maastricht University Medical Center (MUMC), Maastricht, the Netherlands

20. Philip Vincent Charlton

    University of Oxford

    Affiliation as printed

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK;

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK

21. Laura Spiers

    University of Oxford

    Affiliation as printed

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK;

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK

22. Tim J Elliott

    University of Oxford

    Affiliation as printed

    Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK;

    Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK

23. Pallavur V. Sivakumar

    Bristol-Myers Squibb (United States)

    Affiliation as printed

    Bristol-Myers Squibb, Summit, NJ, USA;

    Bristol-Myers Squibb, Summit, NJ, USA

24. Alexander V. Ratushny

    Bristol-Myers Squibb (United States)

    Affiliation as printed

    Bristol-Myers Squibb, Summit, NJ, USA;

    Bristol-Myers Squibb, Summit, NJ, USA

25. Mark Ross Middleton

    University of Oxford

    Affiliation as printed

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK;

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK

26. Dimitra Peppa

    University of Oxford

    Affiliation as printed

    Nuffield Department of Medicine, Old Road Campus, University of Oxford, Oxford OX3 7BN, UK;

    Nuffield Department of Medicine, Old Road Campus, University of Oxford, Oxford OX3 7BN, UK

27. Benjamin P. Fairfax

    University of Oxford

    Affiliation as printed

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK;

    Department of Oncology, University of Oxford, Oxford, OX3 7LF, UK

28. Miriam Mérad

    Icahn School of Medicine at Mount Sinai

    Affiliation as printed

    Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, United States;

    Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, New York, NY 10029, United States

29. Michael Loran Dustin

    University of Oxford · Kennedy Institute of Rheumatology

    Affiliation as printed

    Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, Headington, Oxford OX3 7FY, UK;

    Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Dr, Headington, Oxford OX3 7FY, UK

30. Enas Abu‐Shah

    University of Oxford

    Affiliation as printed

    Sir William Dunn School of Pathology, South Parks Road, University of Oxford, Oxford, OX1 3RE, UK

31. Rachael J. M. Bashford-Rogers corresponding

    University of Oxford

    Affiliation as printed

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK;

    Department of Biochemistry, South Parks Road, University of Oxford, Oxford, OX1 3QU, UK