A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Yin Wu; Dhruva Biswas; Ieva Usaite; Mihaela Angelova; Stefan Boeing; Takahiro Karasaki; Selvaraju Veeriah; Justyna Czyzewska-Khan; Cienne Morton; Magdalene Joseph; Sonya Hessey; James Reading; Andrew Georgiou; Maise Al-Bakir; Nicolai J. Birkbak; Gillian Price; Mohammed Khalil; Keith Kerr; Shirley Richardson; Heather Cheyne; Tracey Cruickshank; Gareth A. Wilson; Rachel Rosenthal; Hugo Aerts; Madeleine Hewish; Girija Anand; Sajid Khan; Kelvin Lau; Michael Sheaff; Peter Schmid; Louise Lim; John Conibear; Roland Schwarz; Tom L. Kaufmann; Matthew Huska; Jacqui Shaw; Joan Riley; Lindsay Primrose; Dean Fennell; Allan Hackshaw; Yenting Ngai; Abigail Sharp; Oliver Pressey; Sean Smith; Nicole Gower; Harjot Kaur Dhanda; Kitty Chan; Sonal Chakraborty; Kevin Litchfield; Krupa Thakkar; TRACERx Consortium; Nicholas McGranahan; Mariam Jamal-Hanjani; Sergio Quezada; Adrian C Hayday; Charles Swanton

doi:10.1038/s43018-022-00376-z

A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Yin Wu^* (Corresponding Author)
, Dhruva Biswas
, Ieva Usaite
, Mihaela Angelova
, Stefan Boeing
, Takahiro Karasaki
, Selvaraju Veeriah
, Justyna Czyzewska-Khan
, Cienne Morton
, Magdalene Joseph
, Sonya Hessey
, James Reading
, Andrew Georgiou
, Maise Al-Bakir
, Nicolai J. Birkbak
, Gillian Price
, Mohammed Khalil
, Keith Kerr
, Shirley Richardson
, Heather Cheyne

Tracey Cruickshank, Gareth A. Wilson, Rachel Rosenthal, Hugo Aerts, Madeleine Hewish, Girija Anand, Sajid Khan, Kelvin Lau, Michael Sheaff, Peter Schmid, Louise Lim, John Conibear, Roland Schwarz, Tom L. Kaufmann, Matthew Huska, Jacqui Shaw, Joan Riley, Lindsay Primrose, Dean Fennell, Allan Hackshaw, Yenting Ngai, Abigail Sharp, Oliver Pressey, Sean Smith, Nicole Gower, Harjot Kaur Dhanda, Kitty Chan, Sonal Chakraborty, Kevin Litchfield, Krupa Thakkar, TRACERx Consortium, Nicholas McGranahan, Mariam Jamal-Hanjani, Sergio Quezada, Adrian C Hayday^* (Corresponding Author), Charles Swanton^* (Corresponding Author)

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

98 Citations (Scopus)

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Abstract

Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8⁺ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA⁻CD27⁻ effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103⁺ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer.

Original language	English
Pages (from-to)	696-709
Number of pages	14
Journal	Nature Cancer
Volume	3
Issue number	6
Early online date	30 May 2022
DOIs	https://doi.org/10.1038/s43018-022-00376-z
Publication status	Published - Jun 2022

Data Availability Statement

The tumor region RNA-seq data, TCR-seq data and flow cytometry data (in each case from the TRACERx study) used or analyzed during the present study are available through the CRUK–University College London Cancer Trials Centre ([email protected]) for academic noncommercial research purposes only, subject to review of a project proposal that will be evaluated by a TRACERx data access committee and any applicable ethical approvals, and entered into an appropriate data access agreement. Restrictions apply to the data availability to safeguard patient sequence data confidentiality, ensure compliance with patient study consent and meet data protection legislation, and due to commercial partnership requirements.

Details of all public datasets obtained from third parties used in the present study are as follows. Blood Atlas Study (https://doi.org/10.1126/science.aax9198) transcriptomic data were downloaded from https://www.proteinatlas.org/about/download. GTEx (www.gtexportal.org) Analysis Release v.8 was accessed via dbGaP (accession no. phs000424.v8.p2). INSPIRE trial (NCT02644369) transcriptomic data were downloaded as SourceData_Fig4.zip from Yang et al. (https://doi.org/10.1038/s41467-021-25432-7). TCGA human LUAD and LUSC transcriptomic data were downloaded directly using the TCGAbiolinks R package derived from TCGA repository: https://portal.gdc.cancer.gov. Source data are provided with this paper.

Code availability
No customized code was used in the present study.

Funding

We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant no. 203141/Z/16/Z) for the generation and initial processing of the RNA-seq data from sorted TILs. We thank S. Bola for technical support and S. Vanloo for administrative support. The GTEx project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Y.W. was supported by a Wellcome Trust Clinical Research Career Development Fellowship (no. 220589/Z/20/Z), an Academy of Medical Sciences Starter Grant for Clinical Lecturers, a National Institute for Health Research (NIHR) Academic Clinical Lectureship and the NIHR University College London Hospitals Biomedical Research Centre. D.B. was supported by funding from the NIHR University College London Hospitals Biomedical Research Centre, the ideas 2 innovation translation scheme at the Francis Crick Institute, the Breast Cancer Research Foundation (BCRF) and a Cancer Research UK (CRUK) Early Detection and Diagnosis Project award. M.J.H. is a CRUK Fellow and has received funding from CRUK, NIHR, Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute which receives its core funding from CRUK (no. FC001169), the UK Medical Research Council (no. FC001169) and the Wellcome Trust (no. FC001169). This research was funded in whole, or in part, by the Wellcome Trust (no. FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. C.S. is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), CRUK Lung Cancer Centre of Excellence (no. C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (no. RP/EA/180007), the NIHR Biomedical Research Centre at University College London Hospitals, the CRUK–University College London Centre, Experimental Cancer Medicine Centre and the BCRF. This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant no. SU2C-AACR-DT23-17 to S. M. Dubinett and A. E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (no. FP7/2007-2013) Consolidator Grant (no. FP7-THESEUS-617844), European Commission ITN (no. FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation program (grant no. 835297), and Chromavision from the European Union’s Horizon 2020 research and innovation program (grant no. 665233).

Funders	Funder number
Wellcome Trust	203141/Z/16/Z, 220589/Z/20/Z, FC001169
Cancer Research UK	FC001169, C11496/A30025
Medical Research Council	FC001169
NOVO Nordisk foundation	ID16584
The Royal Society	RP/EA/180007
Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team	SU2C-AACR-DT23-17
European Research Council	FP7/2007-2013, FP7-THESEUS-617844, FP7-PloidyNet 607722, 835297, 665233

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Cite this

Wu, Y., Biswas, D., Usaite, I., Angelova, M., Boeing, S., Karasaki, T., Veeriah, S., Czyzewska-Khan, J., Morton, C., Joseph, M., Hessey, S., Reading, J., Georgiou, A., Al-Bakir, M., Birkbak, N. J., Price, G., Khalil, M., Kerr, K., Richardson, S., ... Swanton, C. (2022). A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer. Nature Cancer, 3(6), 696-709. https://doi.org/10.1038/s43018-022-00376-z

Wu, Y, Biswas, D, Usaite, I, Angelova, M, Boeing, S, Karasaki, T, Veeriah, S, Czyzewska-Khan, J, Morton, C, Joseph, M, Hessey, S, Reading, J, Georgiou, A, Al-Bakir, M, Birkbak, NJ, Price, G, Khalil, M, Kerr, K, Richardson, S, Cheyne, H, Cruickshank, T, Wilson, GA, Rosenthal, R, Aerts, H, Hewish, M, Anand, G, Khan, S, Lau, K, Sheaff, M, Schmid, P, Lim, L, Conibear, J, Schwarz, R, Kaufmann, TL, Huska, M, Shaw, J, Riley, J, Primrose, L, Fennell, D, Hackshaw, A, Ngai, Y, Sharp, A, Pressey, O, Smith, S, Gower, N, Dhanda, HK, Chan, K, Chakraborty, S, Litchfield, K, Thakkar, K, TRACERx Consortium, McGranahan, N, Jamal-Hanjani, M, Quezada, S, Hayday, AC & Swanton, C 2022, 'A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer', Nature Cancer, vol. 3, no. 6, pp. 696-709. https://doi.org/10.1038/s43018-022-00376-z

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abstract = "Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA−CD27− effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer.",

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AU - Lim, Louise

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AU - Schwarz, Roland

AU - Kaufmann, Tom L.

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AU - Primrose, Lindsay

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N2 - Murine tissues harbor signature γδ T cell compartments with profound yet differential impacts on carcinogenesis. Conversely, human tissue-resident γδ cells are less well defined. In the present study, we show that human lung tissues harbor a resident Vδ1 γδ T cell population. Moreover, we demonstrate that Vδ1 T cells with resident memory and effector memory phenotypes were enriched in lung tumors compared with nontumor lung tissues. Intratumoral Vδ1 T cells possessed stem-like features and were skewed toward cytolysis and helper T cell type 1 function, akin to intratumoral natural killer and CD8+ T cells considered beneficial to the patient. Indeed, ongoing remission post-surgery was significantly associated with the numbers of CD45RA−CD27− effector memory Vδ1 T cells in tumors and, most strikingly, with the numbers of CD103+ tissue-resident Vδ1 T cells in nonmalignant lung tissues. Our findings offer basic insights into human body surface immunology that collectively support integrating Vδ1 T cell biology into immunotherapeutic strategies for nonsmall cell lung cancer.

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A local human Vδ1 T cell population is associated with survival in nonsmall-cell lung cancer

Abstract

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