Joshi, de Massy, and Ismail et al. examined the heterogeneous TCR repertoire within early-stage, untreated non-small cell lung tumors, focusing on the top 1% most frequent TCR sequences. The number of expanded TCRs found ubiquitously in the tumor and the number of expanded TCRs found in only some regions correlated with the number of ubiquitous and regional mutations, respectively, suggesting a neoantigen-driven immune response. Patients with a high number of total or ubiquitous mutations had longer disease-free survival. Ubiquitous TCRs could be non-invasively detected in peripheral blood at the time of tumor resection.
Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations. Expanded TCRs can be subdivided into TCRs found in all tumor regions (ubiquitous) and those present in a subset of regions (regional). The number of ubiquitous and regional TCRs correlates with the number of ubiquitous and regional nonsynonymous mutations, respectively. Expanded TCRs form part of clusters of TCRs of similar sequence, suggestive of a spatially constrained antigen-driven process. CD8(+) tumor-infiltrating lymphocytes harboring ubiquitous TCRs display a dysfunctional tissue-resident phenotype. Ubiquitous TCRs are preferentially detected in the blood at the time of tumor resection as compared to routine follow-up. These findings highlight a noninvasive method to identify and track relevant tumor-reactive TCRs for use in adoptive T cell immunotherapy.
Author Info: (1) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. Department of Medical Oncology, The Royal Marsden NHS Founda
Author Info: (1) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. Department of Medical Oncology, The Royal Marsden NHS Foundation Trust, London, UK. (2) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (3) Division of Infection and Immunity, University College London, London, UK. (4) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (5) Division of Infection and Immunity, University College London, London, UK. (6) Division of Infection and Immunity, University College London, London, UK. (7) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. Department of Medical Oncology, The Royal Marsden NHS Foundation Trust, London, UK. (8) Division of Infection and Immunity, University College London, London, UK. (9) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Bill Lyons Informatics Centre, University College London Cancer Institute, London, UK. (10) Division of Infection and Immunity, University College London, London, UK. Computation, Mathematics and Physics in the Life Sciences and Experimental Biology, Department of Computer Science, University College London, London, UK. (11) Division of Infection and Immunity, University College London, London, UK. (12) Division of Infection and Immunity, University College London, London, UK. (13) Department of Cancer Biology, University College London Cancer Institute, London, UK. (14) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. Department of Medical Oncology, The Royal Marsden NHS Foundation Trust, London, UK. (15) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (16) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (17) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (18) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (19) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (20) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (21) Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (22) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. (23) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (24) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (25) Bill Lyons Informatics Centre, University College London Cancer Institute, London, UK. (26) Bill Lyons Informatics Centre, University College London Cancer Institute, London, UK. (27) University College London Cancer Institute, London, UK. (28) Department of Health Technology, Technical University of Denmark, Lyngby, Denmark. (29) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (30) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. (31) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. (32) Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. c.swanton@crick.ac.uk. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. c.swanton@crick.ac.uk. (33) Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London, UK. s.quezada@ucl.ac.uk. Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. s.quezada@ucl.ac.uk. (34) Division of Infection and Immunity, University College London, London, UK. b.chain@ucl.ac.uk. Department of Computer Sciences, University College London, London, UK. b.chain@ucl.ac.uk.
