Journal article
The T cell differentiation landscape is shaped by tumour mutations in lung cancer
E Ghorani, JL Reading, JY Henry, MR de Massy, R Rosenthal, V Turati, K Joshi, AJS Furness, AB Aissa, SK Saini, S Ramskov, A Georgiou, MW Sunderland, YNS Wong, MV De Mucha, W Day, F Galvez-Cancino, PD Becker, I Uddin, M Ismail Show all
Nature Cancer | NATURE PORTFOLIO | Published : 2020
Abstract
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours, and whether this affects patient outcomes is unknown. Here we paired high-dimensional flow cytometry, exome, single-cell and bulk RNA sequencing from patients with resected, untreated NSCLC to examine these relationships. TMB was associated with compartment-wide T cell differentiation skewing, characterized by loss of TCF7-expressing progenitor-like CD4 T cells, and an increased abundance of ..
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Awarded by European Commission
Funding Acknowledgements
We thank all of the patients who participated in this study and all of the members of the TRACERx Consortium. This work was undertaken with support from the Cancer Research UK (CRUK) and University College London (UCL) Centre (C416/A18088), the CRUK Lung Cancer Centre of Excellence (C5759/A20465), a Cancer Immunotherapy Accelerator Award (CITA-CRUK; C33499/A20265), the National Institute for Health Research UCL Hospitals Biomedical Research Centre (B.C., S.A.Q. and C.S.) and the CRUK and UCL Experimental Cancer Medicine Centre. S.A.Q. received a CRUK Senior Cancer Research Fellowship (C36463/A22246) and is funded by a CRUK Biotherapeutic Program Grant (C36463/A20764), the Rosetrees and Stoneygate trusts (A1388) and a donation from the Khoo Teck Puat UK Foundation via the UCL Cancer Institute Research Trust (539288). C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169, FC001202), the UK Medical Research Council (FC001169, FC001202), and the Wellcome Trust (FC001169, FC001202). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, the Rosetrees Trust, NovoNordisk Foundation (ID16584) and the Breast Cancer Research Foundation (BCRF). This research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. CS receives funding from the European Research Council (ERC) under the European Union's Seventh Framework Programme (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 835297), and Chromavision from the European Union's Horizon 2020 research and innovation programme (grant agreement 665233). B.C. is supported by a CRUK Project Grant. K.S.P. receives funding from the NIHR BTRU in Stem Cells and Immunotherapies (167097), of which he is the Scientific Director. E.G. is funded by a Wellcome Trust Research Training Fellowship. S.R.H. is funded by a grant from the European Research Council, StG 677268 NextDART. The TRACERx study (Clinicaltrials.gov number NCT01888601) is sponsored by UCL. We thank the UCL Cancer Institute Flow Cytometry Translational Technology Platform-in particular Y. Guo, G. Morrow and B. Wilbourn-for support and instrumentation.