Spatial and multi‐omic profiling reveals pericyte‐derived CCL19 as a key prognostic factor in CNS lymphoma

HemaSphere, vol. 10, pp. e70412

Abstract

Abstract Biological mechanisms underlying clinical heterogeneity in central nervous system lymphoma (CNSL) are largely unknown. While previous studies suggest the chemokine CLL19 as a crucial factor for the formation of CNSL in murine models, its role in human disease remains elusive. Here, we performed in‐depth genetic and transcriptomic profiling of 82 CNSL specimens and identified distinct genetic aberrations and tumor cell compositions in lymphomas with high CCL19 expression, both of which were associated with immunosuppressive and anti‐apoptotic signatures. CCL19 levels varied widely across CNSL patients. High CCL19 expression was significantly and independently associated with inferior progression‐free and overall survival. Spatial and single‐nucleus analyses as well as immunohistochemistry revealed pericytes within vessel‐rich areas as the predominant source of CCL19, accompanied by significant co‐localization of CCL19 with its primary receptor CCR7 that was enriched in plasmablast‐like malignant B cells, as well as dendritic cells, NK cells, and CD4 + T cells. Collectively, our study identified pericyte‐derived CCL19 as a novel prognostic marker in CNSL that is associated with unfavorable genetic aberrations and modifications of the immune landscape towards a resting tumor microenvironment. Spatial CCR7 co‐localization suggests avenues for future therapeutic strategies targeting the CCL19–CCR7 axis.

Authors 29

1. Julia C. Kuehn

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

2. Lauritz Miarka

   University of Freiburg

   Affiliation as printed

   Institute of Neuropathology, Faculty of Medicine University of Freiburg Freiburg Germany

3. Roman Sankowski

   University of Freiburg · German Cancer Research Center · Deutsches Konsortium für Translationale Krebsforschung

   Affiliation as printed

   German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ) Heidelberg Germany

   Institute of Neuropathology, Faculty of Medicine University of Freiburg Freiburg Germany

4. Jurik Mutter

   Stanford Medicine · Stanford University

   Affiliation as printed

   Department of Medicine, Divisions of Oncology and Hematology Stanford University Stanford California USA

5. Nicolas Noel Neidert

   University of Freiburg · German Cancer Research Center · University Medical Center Freiburg · Deutsches Konsortium für Translationale Krebsforschung

   Affiliation as printed

   Department of Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

   German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ) Heidelberg Germany

6. Elena Grabis

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

7. Junyi Zhang

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

8. Christian Klingler

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

9. Fabian Hummel

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

10. Lavanya Ranganathan

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

11. Sabine Bleul

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

12. Eliza Maria Lauer

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

13. Dieter Henrik Heiland

    Northwestern University · University of Freiburg · German Cancer Research Center · Friedrich-Alexander-Universität Erlangen-Nürnberg · University Medical Center Freiburg · Universitätsklinikum Erlangen · Robert H. Lurie Comprehensive Cancer Center of Northwestern University · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine Northwestern University Chicago Illinois USA

    Department of Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

    Department of Neurosurgery, University Hospital Erlangen Friedrich‐Alexander University Erlangen‐Nürnberg Erlangen Germany

    German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ) Heidelberg Germany

14. Katharina Müller

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department of Neurology, University Hospital LMU Munich Munich Germany

15. Hans Christian Reinhardt

    Essen University Hospital · Deutsches Konsortium für Translationale Krebsforschung · University of Duisburg-Essen

    Affiliation as printed

    Department of Hematology and Stem Cell Transplantation University Hospital Essen, University Duisburg‐Essen, West German Cancer Center, German Cancer Consortium (DKTK Partner Site Essen), Center for Molecular Biotechnology Essen Germany

16. Sascha Dietrich

    Düsseldorf University Hospital

    Affiliation as printed

    Department of Hematology, Oncology and Clinical Immunology University Hospital Düsseldorf Düsseldorf Germany

17. Gerald Illerhaus

    Klinikum Stuttgart

    Affiliation as printed

    Clinic of Hematology, Oncology, Stem Cell Transplantation and Palliative Care, Klinikum Stuttgart Stuttgart Germany

18. Louisa von Baumgarten

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department of Neurology, University Hospital LMU Munich Munich Germany

19. Stefan Alig

    Essen University Hospital · Deutsches Konsortium für Translationale Krebsforschung · University of Duisburg-Essen

    Affiliation as printed

    Department of Hematology and Stem Cell Transplantation University Hospital Essen, University Duisburg‐Essen, West German Cancer Center, German Cancer Consortium (DKTK Partner Site Essen), Center for Molecular Biotechnology Essen Germany

20. Maximilian Diehn

    Stanford Medicine

    Affiliation as printed

    Department of Radiation Oncology Stanford University Medical Center Stanford California USA

21. Bastian Sajonz

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Stereotactic and Functional Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

22. Jürgen Beck

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

23. Volker A. Coenen

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Stereotactic and Functional Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

24. Marco Prinz

    University of Freiburg

    Affiliation as printed

    Institute of Neuropathology, Faculty of Medicine University of Freiburg Freiburg Germany

    Signalling Research Centres BIOSS and CIBSS University of Freiburg Freiburg Germany

25. Elisabeth Schorb

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

26. Ash A. Alizadeh

    Stanford Medicine · Stanford University

    Affiliation as printed

    Department of Medicine, Divisions of Oncology and Hematology Stanford University Stanford California USA

27. Justus Duyster

    University of Freiburg · University Medical Center Freiburg

    Affiliation as printed

    Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

28. Peter Christoph Reinacher Aachen Fraunhofer Institute for Laser Technology Aachen Germany

    University of Freiburg · University Medical Center Freiburg · Fraunhofer Institute for Laser Technology

    Affiliation as printed

    Department of Stereotactic and Functional Neurosurgery, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

    Fraunhofer Institute for Laser Technology (ILT) Aachen Germany

29. Florian Scherer

    University of Freiburg · German Cancer Research Center · University Medical Center Freiburg · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine University of Freiburg Freiburg Germany

    German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ) Heidelberg Germany