Single-cell integration and multi-modal profiling reveals phenotypes and spatial organization of neutrophils in colorectal cancer

Cancer Cell, vol. 44, pp. 146–165.e14

Abstract

SUMMARY The immune composition of the tumor microenvironment (TME) has a major impact on the therapeutic response and clinical outcome in patients with colorectal cancer (CRC). Here, we comprehensively characterize the TME at the single-cell level by first building a large-scale atlas that integrates 4.27 million single cells from 1,670 patient samples. We then complemented the atlas with single-cell profiles from four CRC cohorts with 266 patients, including cells with low mRNA content, spatial transcriptional profiles from 3.7 million cells, and protein profiles from 0.7 million cells. The analysis of the atlas allows refined tumor classification into four immune phenotypes: immune desert, B cell enriched, T cell enriched, and myeloid cell enriched subtypes. Within the myeloid compartment we uncover distinct subpopulations of neutrophils that acquire new functional properties in blood and in the TME, including anti-tumorigenic capabilities. Further, spatial multimodal single-cell profiling reveals that neutrophils are organized in clusters within distinct functional niches. Finally, using an orthotopic mouse model we show that cancer-derived systemic signals modify neutrophil production in the bone marrow, providing evidence for tumor-induced granulopoiesis. Our study provides a big data resource for the CRC and suggests novel therapeutic strategies targeting neutrophils.

Authors 47

1. Valentin Marteau

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

2. Niloofar Nemati

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

3. Kristina Handler

   University of Zurich

   Affiliation as printed

   Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

4. Deeksha Raju

   University of Zurich

   Affiliation as printed

   Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

5. Alexander Kirchmair

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

6. Dietmar Rieder

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

7. Erika Kvalem Soto

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

8. Georgios Fotakis

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

9. G. de Lange

   University of Zurich

   Affiliation as printed

   Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

10. Sandro Carollo

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

11. Nina Boeck

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

12. Alessia Rossi

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

13. Sophia Daum

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria

14. Alexandra Scheiber

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria

15. Arno Amann

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria

16. Andreas Seeber

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria

17. Elisabeth Gasser

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Department of Visceral, Transplant and Thoracic Surgery, Medical University Innsbruck, Innsbruck, Austria

18. Steffen Ormanns

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Institute of General Pathology, Medical University Innsbruck, Innsbruck, Austria

19. Michael Günther

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Institute of General Pathology, Medical University Innsbruck, Innsbruck, Austria

20. Agnieszka Martowicz

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria; Tyrolpath Obrist Brunhuber GmbH, Zams, Austria

21. Zuzana Loncová

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

22. Giorgia Lamberti

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

23. Krogsdam Anne

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

24. Michela Carlet

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

25. Lena Horvath

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria

26. Marie Theres Eling

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Department of Therapeutic Radiology and Oncology, Medical University Innsbruck, Innsbruck, Austria

27. Hassan Fazilaty

    University of Zurich

    Affiliation as printed

    Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland

28. Tomáš Valenta

    University of Zurich · Czech Academy of Sciences, Institute of Molecular Genetics

    Affiliation as printed

    Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland; Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic

29. Gregor Sturm

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria

30. Sieghart Sopper

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria

31. Andreas Pircher

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria

32. Patrizia Stoitzner

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck, Innsbruck, Austria

33. PJ Wild

    Goethe University Frankfurt

    Affiliation as printed

    Senckenberg Institute of Pathology, Goethe University Frankfurt, Frankfurt, Germany; University Cancer Center Frankfurt (UCT), Frankfurt, Germany

34. Patrick Welker

    Goethe University Frankfurt

    Affiliation as printed

    Senckenberg Institute of Pathology, Goethe University Frankfurt, Frankfurt, Germany

35. Pascal J. May

    Goethe University Frankfurt

    Affiliation as printed

    Senckenberg Institute of Pathology, Goethe University Frankfurt, Frankfurt, Germany

36. Paul K. Ziegler

    Goethe University Frankfurt

    Affiliation as printed

    Senckenberg Institute of Pathology, Goethe University Frankfurt, Frankfurt, Germany; University Cancer Center Frankfurt (UCT), Frankfurt, Germany

37. Markus Tschurtschenthaler

    TUM Klinikum · Technical University of Munich

    Affiliation as printed

    Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum Rechts der Isar, School of Medicine & Health, Technical University of Munich, Munich, Germany

38. Daniel Neureiter

    Paracelsus Medical University

    Affiliation as printed

    Institute of Pathology, Paracelsus Medical University, Salzburg, Austria

39. Florian Huemer

    Paracelsus Medical University

    Affiliation as printed

    Department of Internal Medicine III, Paracelsus Medical University, Salzburg, Austria

40. Richard Greil

    Paracelsus Medical University

    Affiliation as printed

    Department of Internal Medicine III, Paracelsus Medical University, Salzburg, Austria

41. Lukas Weiss

    Paracelsus Medical University · Austrian Breast & Colorectal Cancer Study Group

    Affiliation as printed

    Department of Internal Medicine III, Paracelsus Medical University, Salzburg, Austria; Austrian Breast & Colorectal Cancer Study Group (ABCSG), Vienna, Austria

42. Marieke E. Ijsselsteijn Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

43. Noel F.C.C. de Miranda Aachen Department of Pathology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

44. Dominik Wolf corresponding

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: dominik.wolf@i-med.ac.at

45. Isabelle Catherine Arnold corresponding

    University of Zurich

    Affiliation as printed

    Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland; Comprehensive Cancer Center Zürich, Zürich, Switzerland. Electronic address: arnold@immunology.uzh.ch

46. Stefan Salcher corresponding

    Innsbruck Medical University · Universität Innsbruck · Tyrolean Cancer Research Institute

    Affiliation as printed

    Department of Internal Medicine V, Haematology & Oncology, Comprehensive Cancer Center Innsbruck and Tyrolean Cancer Research Institute, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: stefan.salcher@i-med.ac.at

47. Zlatko Trajanoski corresponding

    Innsbruck Medical University · Universität Innsbruck

    Affiliation as printed

    Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: zlatko.trajanoski@i-med.ac.at