Multimodal analysis unveils tumor microenvironment heterogeneity linked to immune activity and evasion

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Summary The cellular and molecular heterogeneity of tumors is a major obstacle to cancer immunotherapy. Here, we use a systems biology approach to derive a signature of the main sources of heterogeneity in the tumor microenvironment (TME) from lung cancer transcriptomic data. We demonstrate that this signature, which we called iHet , is conserved in different cancers and associated with antitumor immunity. Through the analysis of single-cell and spatial transcriptomics data, we trace back the cellular origin of the variability that explains the iHet signature. Finally, we demonstrate that iHet has predictive value for cancer immunotherapy, which can be further improved by disentangling three major determinants of anticancer immune responses: activity of immune cells, immune infiltration or exclusion, and cancer-cell foreignness. This work shows how transcriptomics data can be integrated to derive a holistic representation of the phenotypic heterogeneity of the TME, and ultimately to determine its unfolding and fate during immunotherapy with immune checkpoint blockers.

Authors 11

1. Óscar Lapuente-Santana

   Spanish National Cancer Research Centre · Eindhoven University of Technology

   Affiliation as printed

   Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain

   Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, 5612 AZ Eindhoven, the Netherlands

   Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), 809 Madrid, Spain

   Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, 562 AZ Eindhoven, the Netherlands

2. Gregor Sturm

   Boehringer Ingelheim (Germany) · Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

   Boehringer Ingelheim International Pharma GmbH & Co KG, Biberach, Germany

3. Markus Außerhofer

   Universität Innsbruck

   Affiliation as printed

   Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 6020 Innsbruck, Austria

   Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 020 Innsbruck, Austria

4. Constantin Zackl

   Universität Innsbruck

   Affiliation as printed

   Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 6020 Innsbruck, Austria

   Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 020 Innsbruck, Austria

5. Maria Zopoglou

   Universität Innsbruck

   Affiliation as printed

   Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 6020 Innsbruck, Austria

   Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 020 Innsbruck, Austria

6. Nicholas McGranahan

   University College London

   Affiliation as printed

   Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK

   Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK

7. Dietmar Rieder

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

8. Zlatko Trajanoski

   Innsbruck Medical University · Universität Innsbruck

   Affiliation as printed

   Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria

9. Noel F.C.C. de Miranda Aachen Department of Pathology, Leiden University Medical Centre

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

10. Federica Eduati

    Eindhoven University of Technology

    Affiliation as printed

    Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, 5612 AZ Eindhoven, the Netherlands

    Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, 562 AZ Eindhoven, the Netherlands

11. Francesca Finotello corresponding

    Universität Innsbruck

    Affiliation as printed

    Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 6020 Innsbruck, Austria

    Department of Molecular Biology, Digital Science Center (DiSC), University of Innsbruck, 020 Innsbruck, Austria