Dijkstra et al. generated patient-derived organoid sublines from spatially distinct tumor regions and separate clones within individual regions of 3 NSCLC samples, and also expanded tumor-reactive autologous TILs or donor-derived NK cells. Tumor cell subpopulations from the same patient showed substantial heterogeneity in their capacity to elicit a T cell or NK cell response, both within and across tumor regions. Genetically distinct subclones represented immune-evasive and non-evasive subpopulations through both antigen-dependent and -independent mechanisms, but these were not predictable based on genetic or transcriptomic features.
Contributed by Shishir Pant
ABSTRACT: Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.
Author Info: (1) Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Evolution and Genome Instability Laboratory, The Francis C
Author Info: (1) Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Oncode Institute, Utrecht, the Netherlands. Electronic address: k.dijkstra@nki.nl. (2) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Tumor ImmunoGenomics and Immunosurveillance Laboratory, University College London Cancer Institute, University College London, London, UK. (3) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Immunology Unit, Immune Regulation and Tumor Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK. (4) Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (5) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Immunology Unit, Immune Regulation and Tumor Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK; Immune Regulation Laboratory, Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom. (6) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (7) Cancer Immunology Unit, Immune Regulation and Tumor Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK. (8) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (9) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (10) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Epithelial Cell Biology in ENT Research (EpiCENTR) Group, Developmental Biology and Cancer Department, Great Ormond Street UCL Institute of Child Health, University College London, London, UK. (11) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (12) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (13) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (14) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (15) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (16) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (17) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Tumor ImmunoGenomics and Immunosurveillance Laboratory, University College London Cancer Institute, University College London, London, UK; Division of Medicine, University College London, London, UK. (18) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (19) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Department of Cellular Pathology, University College London Hospital, London, UK. (20) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (21) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (22) Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (23) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (24) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (25) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (26) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Immunology Unit, Immune Regulation and Tumor Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK. (27) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK. (28) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK. (29) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (30) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Tumor ImmunoGenomics and Immunosurveillance Laboratory, University College London Cancer Institute, University College London, London, UK. (31) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Pre-Cancer Immunology Laboratory, University College London Cancer Institute, London, UK. (32) University College London Cancer Institute, London, UK; Division of Infection and Immunity, University College London, London, UK. (33) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Immunology Unit, Immune Regulation and Tumor Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK. Electronic address: s.quezada@ucl.ac.uk. (34) Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. Electronic address: e.voest@nki.nl. (35) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK. Electronic address: charles.swanton@crick.ac.uk.
