ImmuneLENS characterizes systemic immune dysregulation in aging and cancer

Robert Bentham; Thomas P. Jones; James R.M. Black; Carlos Martinez-Ruiz; Michelle Dietzen; Maria Litovchenko; Kerstin Thol; Thomas B.K. Watkins; Chris Bailey; Oriol Pich; Zhihui Zhang; Peter Van Loo; Mathew Thomas; Jennifer Whiteley; Nikos Kostoulas; Rocco Bilancia; Mo Asif; Alan Kirk; John Le Quesne; Craig Dick; Andrew Kidd; Kevin G. Blyth; Peter Russell; Lily Robinson; Michael J. Shackcloth; Sarah Danson; Madeleine Hewish; Chiara Proli; Pratibha Shah; Nadia Fernandes; Sarah Booth; Mpho Malima; Daniel Kaniu; Silviu I. Buderi; Sofina Begum; Hema Chavan; Anand Devaraj; Lyn Ambrose; Harshil Bhayani; Hilgardt Raubenheimer; Alexandra Rice; Simon Jordan; Paulo De Sousa; Andrew G. Nicholson; Eric Lim; Judith Cave; Aiman Alzetani; Patricia Georg; Serena Chee; Mairead MacKenzie; Genomics England Consortium; TRACERx Consortium; Hugo J.W.L. Aerts; Nicholas McGranahan

doi:10.1038/s41588-025-02086-5

ImmuneLENS characterizes systemic immune dysregulation in aging and cancer

Robert Bentham, Thomas P. Jones, James R.M. Black, Carlos Martinez-Ruiz, Michelle Dietzen, Maria Litovchenko, Kerstin Thol, Thomas B.K. Watkins, Chris Bailey, Oriol Pich, Zhihui Zhang, Peter Van Loo, Mathew Thomas, Jennifer Whiteley, Nikos Kostoulas, Rocco Bilancia, Mo Asif, Alan Kirk, John Le Quesne, Craig DickAndrew Kidd, Kevin G. Blyth, Peter Russell, Lily Robinson, Michael J. Shackcloth, Sarah Danson, Madeleine Hewish, Chiara Proli, Pratibha Shah, Nadia Fernandes, Sarah Booth, Mpho Malima, Daniel Kaniu, Silviu I. Buderi, Sofina Begum, Hema Chavan, Anand Devaraj, Lyn Ambrose, Harshil Bhayani, Hilgardt Raubenheimer, Alexandra Rice, Simon Jordan, Paulo De Sousa, Andrew G. Nicholson, Eric Lim, Judith Cave, Aiman Alzetani, Patricia Georg, Serena Chee, Mairead MacKenzie, Genomics England Consortium, TRACERx Consortium, Hugo J.W.L. Aerts, Nicholas McGranahan^*

^*Corresponding author for this work

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

Abstract

Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.

Original language	English
Article number	305
Pages (from-to)	694-705
Number of pages	12
Journal	Nature Genetics
Volume	57
Issue number	3
DOIs	https://doi.org/10.1038/s41588-025-02086-5
Publication status	Published - Mar 2025

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Bentham, R., Jones, T. P., Black, J. R. M., Martinez-Ruiz, C., Dietzen, M., Litovchenko, M., Thol, K., Watkins, T. B. K., Bailey, C., Pich, O., Zhang, Z., Van Loo, P., Thomas, M., Whiteley, J., Kostoulas, N., Bilancia, R., Asif, M., Kirk, A., Le Quesne, J., ... McGranahan, N. (2025). ImmuneLENS characterizes systemic immune dysregulation in aging and cancer. Nature Genetics, 57(3), 694-705. Article 305. https://doi.org/10.1038/s41588-025-02086-5

@article{85666172d67d400483c7c34d8b79c7b6,

title = "ImmuneLENS characterizes systemic immune dysregulation in aging and cancer",

abstract = "Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.",

author = "Robert Bentham and Jones, {Thomas P.} and Black, {James R.M.} and Carlos Martinez-Ruiz and Michelle Dietzen and Maria Litovchenko and Kerstin Thol and Watkins, {Thomas B.K.} and Chris Bailey and Oriol Pich and Zhihui Zhang and {Van Loo}, Peter and Mathew Thomas and Jennifer Whiteley and Nikos Kostoulas and Rocco Bilancia and Mo Asif and Alan Kirk and {Le Quesne}, John and Craig Dick and Andrew Kidd and Blyth, {Kevin G.} and Peter Russell and Lily Robinson and Shackcloth, {Michael J.} and Sarah Danson and Madeleine Hewish and Chiara Proli and Pratibha Shah and Nadia Fernandes and Sarah Booth and Mpho Malima and Daniel Kaniu and Buderi, {Silviu I.} and Sofina Begum and Hema Chavan and Anand Devaraj and Lyn Ambrose and Harshil Bhayani and Hilgardt Raubenheimer and Alexandra Rice and Simon Jordan and {De Sousa}, Paulo and Nicholson, {Andrew G.} and Eric Lim and Judith Cave and Aiman Alzetani and Patricia Georg and Serena Chee and Mairead MacKenzie and {Genomics England Consortium} and {TRACERx Consortium} and Aerts, {Hugo J.W.L.} and Nicholas McGranahan",

note = "Funding Information: R.B. is supported by the National Institute of Health and Care Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospitals. T.P.J. is supported by the Cancer Research UK City of London Centre. J.R.M.B. is supported by Cancer Research UK. C.P. is supported by the Francis Crick Institute. C.M.-R. is supported by the Rosetrees (M630) and Wellcome trusts. M.D. is supported by CRUK and the Lung Cancer Centre of Excellence. M.L. is supported by the Cancer Research UK City of London Centre. K.T. is supported by the Radiation Research Unit at the Cancer Research UK City of London Centre Award (C7893/A28990). T.B.K.W. is supported by the Francis Crick Institute and by the Marie Curie ITN Project PLOIDYNET (FP7-PEOPLE-2013, 607722), the Breast Cancer Research Foundation (BCRF), a Royal Society Research Professorships Enhancement Award (RP/EA/180007) and the Foulkes Foundation. O.P. is supported by funding from the European Union\u2019s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant (101068227). C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). For 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 Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; Novo Nordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007 and RF\\ERE\\231118); NIHR University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the BCRF (US; BCRF-22-157); Cancer Research UK Early Detection and Diagnosis Primer Award (grant EDDPMA-Nov21/100034); the Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP) and ASPIRE Phase II Award (grant 23-034-ASP). C.S. is in receipt of an European Research Council (ERC) Advanced Grant (PROTEUS) from the European Research Council under the European Union\u2019s Horizon 2020 research and innovation program (grant 835297). P.V.L. is a CPRIT Scholar in Cancer Research and acknowledges CPRIT grant support (RR210006). N.M. was a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z), and also receives funding from a CRUK Programme Foundation Award (DRCPFA-Nov23/100003) and a CRUK Biomarker Project Award (CRCBPA-Mar24/100001), the Rosetrees Trust, the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. Funding Information: This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. Funding Information: TRACERx is funded by Cancer Research UK (C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre, which has a core grant from Cancer Research UK (CRUK) (C444/A15953). We gratefully acknowledge the patients and relatives who participated in the TRACERx study. We thank all site personnel, investigators, funders and industry partners who supported the generation of the data within this study. Funding Information: This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (MR/L016311/1). In particular, we acknowledge the support of the High-Performance Computing at the Francis Crick Institute as well as the UCL Department of Computer Science Cluster and the support team. In addition, this work was supported by the CRUK City of London Centre Award (C7893/A26233). Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = mar,

doi = "10.1038/s41588-025-02086-5",

language = "English",

volume = "57",

pages = "694--705",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

}

Bentham, R, Jones, TP, Black, JRM, Martinez-Ruiz, C, Dietzen, M, Litovchenko, M, Thol, K, Watkins, TBK, Bailey, C, Pich, O, Zhang, Z, Van Loo, P, Thomas, M, Whiteley, J, Kostoulas, N, Bilancia, R, Asif, M, Kirk, A, Le Quesne, J, Dick, C, Kidd, A, Blyth, KG, Russell, P, Robinson, L, Shackcloth, MJ, Danson, S, Hewish, M, Proli, C, Shah, P, Fernandes, N, Booth, S, Malima, M, Kaniu, D, Buderi, SI, Begum, S, Chavan, H, Devaraj, A, Ambrose, L, Bhayani, H, Raubenheimer, H, Rice, A, Jordan, S, De Sousa, P, Nicholson, AG, Lim, E, Cave, J, Alzetani, A, Georg, P, Chee, S, MacKenzie, M, Genomics England Consortium, TRACERx Consortium, Aerts, HJWL & McGranahan, N 2025, 'ImmuneLENS characterizes systemic immune dysregulation in aging and cancer', Nature Genetics, vol. 57, no. 3, 305, pp. 694-705. https://doi.org/10.1038/s41588-025-02086-5

TY - JOUR

T1 - ImmuneLENS characterizes systemic immune dysregulation in aging and cancer

AU - Bentham, Robert

AU - Jones, Thomas P.

AU - Black, James R.M.

AU - Martinez-Ruiz, Carlos

AU - Dietzen, Michelle

AU - Litovchenko, Maria

AU - Thol, Kerstin

AU - Watkins, Thomas B.K.

AU - Bailey, Chris

AU - Pich, Oriol

AU - Zhang, Zhihui

AU - Van Loo, Peter

AU - Thomas, Mathew

AU - Whiteley, Jennifer

AU - Kostoulas, Nikos

AU - Bilancia, Rocco

AU - Asif, Mo

AU - Kirk, Alan

AU - Le Quesne, John

AU - Dick, Craig

AU - Kidd, Andrew

AU - Blyth, Kevin G.

AU - Russell, Peter

AU - Robinson, Lily

AU - Shackcloth, Michael J.

AU - Danson, Sarah

AU - Hewish, Madeleine

AU - Proli, Chiara

AU - Shah, Pratibha

AU - Fernandes, Nadia

AU - Booth, Sarah

AU - Malima, Mpho

AU - Kaniu, Daniel

AU - Buderi, Silviu I.

AU - Begum, Sofina

AU - Chavan, Hema

AU - Devaraj, Anand

AU - Ambrose, Lyn

AU - Bhayani, Harshil

AU - Raubenheimer, Hilgardt

AU - Rice, Alexandra

AU - Jordan, Simon

AU - De Sousa, Paulo

AU - Nicholson, Andrew G.

AU - Lim, Eric

AU - Cave, Judith

AU - Alzetani, Aiman

AU - Georg, Patricia

AU - Chee, Serena

AU - MacKenzie, Mairead

AU - Genomics England Consortium

AU - TRACERx Consortium

AU - Aerts, Hugo J.W.L.

AU - McGranahan, Nicholas

N1 - Funding Information: R.B. is supported by the National Institute of Health and Care Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospitals. T.P.J. is supported by the Cancer Research UK City of London Centre. J.R.M.B. is supported by Cancer Research UK. C.P. is supported by the Francis Crick Institute. C.M.-R. is supported by the Rosetrees (M630) and Wellcome trusts. M.D. is supported by CRUK and the Lung Cancer Centre of Excellence. M.L. is supported by the Cancer Research UK City of London Centre. K.T. is supported by the Radiation Research Unit at the Cancer Research UK City of London Centre Award (C7893/A28990). T.B.K.W. is supported by the Francis Crick Institute and by the Marie Curie ITN Project PLOIDYNET (FP7-PEOPLE-2013, 607722), the Breast Cancer Research Foundation (BCRF), a Royal Society Research Professorships Enhancement Award (RP/EA/180007) and the Foulkes Foundation. O.P. is supported by funding from the European Union\u2019s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant (101068227). C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041) and the Wellcome Trust (CC2041). For 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 Cancer Research UK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; Novo Nordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007 and RF\\ERE\\231118); NIHR University College London Hospitals Biomedical Research Centre; the Cancer Research UK-University College London Centre; Experimental Cancer Medicine Centre; the BCRF (US; BCRF-22-157); Cancer Research UK Early Detection and Diagnosis Primer Award (grant EDDPMA-Nov21/100034); the Mark Foundation for Cancer Research Aspire Award (grant 21-029-ASP) and ASPIRE Phase II Award (grant 23-034-ASP). C.S. is in receipt of an European Research Council (ERC) Advanced Grant (PROTEUS) from the European Research Council under the European Union\u2019s Horizon 2020 research and innovation program (grant 835297). P.V.L. is a CPRIT Scholar in Cancer Research and acknowledges CPRIT grant support (RR210006). N.M. was a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z), and also receives funding from a CRUK Programme Foundation Award (DRCPFA-Nov23/100003) and a CRUK Biomarker Project Award (CRCBPA-Mar24/100001), the Rosetrees Trust, the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. Funding Information: This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. Funding Information: TRACERx is funded by Cancer Research UK (C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre, which has a core grant from Cancer Research UK (CRUK) (C444/A15953). We gratefully acknowledge the patients and relatives who participated in the TRACERx study. We thank all site personnel, investigators, funders and industry partners who supported the generation of the data within this study. Funding Information: This project was enabled through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (MR/L016311/1). In particular, we acknowledge the support of the High-Performance Computing at the Francis Crick Institute as well as the UCL Department of Computer Science Cluster and the support team. In addition, this work was supported by the CRUK City of London Centre Award (C7893/A26233). Publisher Copyright: © The Author(s) 2025.

PY - 2025/3

Y1 - 2025/3

N2 - Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.

AB - Recognition and elimination of pathogens and cancer cells depend on the adaptive immune system. Thus, accurate quantification of immune subsets is vital for precision medicine. We present immune lymphocyte estimation from nucleotide sequencing (ImmuneLENS), which estimates T cell and B cell fractions, class switching and clonotype diversity from whole-genome sequencing data at depths as low as 5× coverage. By applying ImmuneLENS to the 100,000 Genomes Project, we identify genes enriched with somatic mutations in T cell-rich tumors, significant sex-based differences in circulating T cell fraction and demonstrated that the circulating T cell fraction in patients with cancer is significantly lower than in healthy individuals. Low circulating B cell fraction was linked to increased cancer incidence. Finally, circulating T cell abundance was more prognostic of 5-year cancer survival than infiltrating T cells.

U2 - 10.1038/s41588-025-02086-5

DO - 10.1038/s41588-025-02086-5

M3 - Article

SN - 1061-4036

VL - 57

SP - 694

EP - 705

JO - Nature Genetics

JF - Nature Genetics

IS - 3

M1 - 305

ER -

ImmuneLENS characterizes systemic immune dysregulation in aging and cancer

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