Journal article

The T cell differentiation landscape is shaped by tumour mutations in lung cancer

Ehsan Ghorani, James L Reading, Jake Y Henry, Marc Robert de Massy, Rachel Rosenthal, Virginia Turati, Kroopa Joshi, Andrew JS Furness, Assma Ben Aissa, Sunil Kumar Saini, Sofie Ramskov, Andrew Georgiou, Mariana Werner Sunderland, Yien Ning Sophia Wong, Maria Vila De Mucha, William Day, Felipe Galvez-Cancino, Pablo D Becker, Imran Uddin, Mazlina Ismail Show all

NATURE CANCER | SPRINGERNATURE | 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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Grants

Awarded by University College London (UCL) Centre


Awarded by CRUK Lung Cancer Centre of Excellence


Awarded by Cancer Immunotherapy Accelerator Award (CITA-CRUK)


Awarded by CRUK Senior Cancer Research Fellowship


Awarded by CRUK Biotherapeutic Program Grant


Awarded by Rosetrees trust


Awarded by Khoo Teck Puat UK Foundation via the UCL Cancer Institute Research Trust


Awarded by Cancer Research UK


Awarded by UK Medical Research Council


Awarded by Wellcome Trust


Awarded by NovoNordisk Foundation


Awarded by Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant


Awarded by European Research Council (ERC) under the European Union


Awarded by European Commission ITN


Awarded by European Research Council under the European Union


Awarded by Chromavision from the European Union's Horizon 2020 research and innovation programme


Awarded by NIHR BTRU in Stem Cells and Immunotherapies


Awarded by European Research Council


Awarded by UCL


Awarded by Stoneygate trust


Awarded by The Francis Crick Institute


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.