Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer

Max Backman; Carina Strell; Amanda Lindberg; Johanna S M Mattsson; Hedvig Elfving; Hans Brunnström; Aine O'Reilly; Martina Bosic; Miklos Gulyas; Johan Isaksson; Johan Botling; Klas Kärre; Karin Jirström; Kristina Lamberg; Fredrik Pontén; Karin Leandersson; Artur Mezheyeuski; Patrick Micke

doi:10.1016/j.ejca.2023.02.012

Spatial immunophenotyping of the tumour microenvironment in non-small cell lung cancer

Eur J Cancer. 2023 May:185:40-52. doi: 10.1016/j.ejca.2023.02.012. Epub 2023 Feb 24.

Authors

Max Backman¹, Carina Strell², Amanda Lindberg¹, Johanna S M Mattsson¹, Hedvig Elfving¹, Hans Brunnström³, Aine O'Reilly⁴, Martina Bosic⁵, Miklos Gulyas¹, Johan Isaksson⁶, Johan Botling¹, Klas Kärre⁷, Karin Jirström⁸, Kristina Lamberg⁹, Fredrik Pontén¹, Karin Leandersson¹⁰, Artur Mezheyeuski¹¹, Patrick Micke¹²

Affiliations

¹ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
² Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
³ Division of Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
⁴ Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
⁵ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
⁶ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Department of Respiratory Medicine, Gävle Hospital, Gävle, Sweden.
⁷ Department of Microbiology, Cell and Tumor Biology, Karolinska Institutet, Stockholm, Sweden.
⁸ Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
⁹ Department of Respiratory Medicine, Akademiska Sjukhuset, Uppsala, Sweden.
¹⁰ Department of Translational Medicine, Lund University, Skånes University Hospital, Malmö, Sweden.
¹¹ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden; Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
¹² Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. Electronic address: patrick.micke@igp.uu.se.

PMID: 36963351
DOI: 10.1016/j.ejca.2023.02.012

Abstract

Introduction: Immune cells in the tumour microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterise the spatial immune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).

Methods: We established a multiplexed fluorescence imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4-Eff), CD4 regulatory cells (CD4-Treg), CD8 effector cells (CD8-Eff), CD8 regulatory cells (CD8-Treg), B-cells, natural killer cells, natural killer T-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs).

Results: CD4-Eff cells, CD8-Eff cells and M1 macrophages were the most abundant immune cells invading the tumour cell compartment and indicated a patient group with a favourable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4-Eff, CD4-Treg, CD8-Treg, B-cells and pDCs) were independently associated with longer survival. However, when these immune cells were located close to CD8-Treg cells, the favourable impact was attenuated. In the multivariable Cox regression model, including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8-Treg-B-cells, CD8-Eff-cancer cells and B-cells-CD4-Treg) demonstrated positive prognostic impact, whereas short M2-M1 distances were prognostically unfavourable.

Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is crucial for diagnostic use.

Keywords: Checkpoint therapy; Immune cell infiltration; Lung cancer; Multiplex imaging; NSCLC; Tumour microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Carcinoma, Non-Small-Cell Lung* / pathology
Humans
Immunophenotyping
Lung Neoplasms* / pathology
Prognosis
Tumor Microenvironment