An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancersResearch in context
Artur Mezheyeuski,
Max Backman,
Johanna Mattsson,
Alfonso Martín-Bernabé,
Chatarina Larsson,
Ina Hrynchyk,
Klara Hammarström,
Simon Ström,
Joakim Ekström,
Siarhei Mauchanski,
Salome Khelashvili,
Amanda Lindberg,
Margrét Agnarsdóttir,
Per-Henrik Edqvist,
Jutta Huvila,
Ulrika Segersten,
Per-Uno Malmström,
Johan Botling,
Björn Nodin,
Charlotta Hedner,
David Borg,
Jenny Brändstedt,
Hanna Sartor,
Karin Leandersson,
Bengt Glimelius,
Anna Portyanko,
Fredrik Ponten,
Karin Jirström,
Patrick Micke,
Tobias Sjöblom
Affiliations
Artur Mezheyeuski
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Max Backman
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Johanna Mattsson
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Alfonso Martín-Bernabé
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Karolinska vägen, A2:07, 171 64 Solna, Sweden
Chatarina Larsson
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Ina Hrynchyk
City Clinical Pathologoanatomic Bureau, Minsk 220116, Republic of Belarus
Klara Hammarström
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Simon Ström
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Joakim Ekström
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Siarhei Mauchanski
N.N. Alexandrov National Cancer Centre of Belarus, Lesnoy, Minsk, 223040, Republic of Belarus
Salome Khelashvili
N.N. Alexandrov National Cancer Centre of Belarus, Lesnoy, Minsk, 223040, Republic of Belarus
Amanda Lindberg
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Margrét Agnarsdóttir
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Per-Henrik Edqvist
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Jutta Huvila
Department of Pathology, University of Turku, 20500 Åbo, Finland
Ulrika Segersten
Department of Surgical Sciences, Uppsala University, Akademiska sjukhuset, 751 85 Uppsala, Sweden
Per-Uno Malmström
Department of Surgical Sciences, Uppsala University, Akademiska sjukhuset, 751 85 Uppsala, Sweden
Johan Botling
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Björn Nodin
Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, 221 85 Lund, Sweden
Charlotta Hedner
Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, 221 85 Lund, Sweden
David Borg
Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, 221 85 Lund, Sweden
Jenny Brändstedt
Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, 221 85 Lund, Sweden
Hanna Sartor
Diagnostic Radiology, Department of Translational Medicine, Lund University, Skåne University Hospital, Carl-Bertil Laurells gata 9, 20502 Malmö, Sweden
Karin Leandersson
Cancer Immunology, Department of Translational Medicine, Lund University, J Waldenströms gata 35, 214 28 Malmö, Sweden
Bengt Glimelius
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Anna Portyanko
N.N. Alexandrov National Cancer Centre of Belarus, Lesnoy, Minsk, 223040, Republic of Belarus
Fredrik Ponten
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Karin Jirström
Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, 221 85 Lund, Sweden
Patrick Micke
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden
Tobias Sjöblom
Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, 751 85 Uppsala, Sweden; Corresponding author.
Summary: Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression. Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations. Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy. Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types. Funding: Swedish Cancer Society, Lions Cancer Foundation, Selanders Foundation, P.O. Zetterling Foundation, U-CAN supported by SRA CancerUU, Uppsala University and Region Uppsala.
