Abstract
Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27–CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGnIFICAnCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcino-genesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.
Original language | English (US) |
---|---|
Pages (from-to) | 1489-1499 |
Number of pages | 11 |
Journal | Cancer discovery |
Volume | 10 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2020 |
ASJC Scopus subject areas
- Oncology
Access to Document
Other files and links
Fingerprint Dive into the research topics of 'Immune surveillance in clinical regression of preinvasive squamous cell lung cancer'. Together they form a unique fingerprint.
Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Immune surveillance in clinical regression of preinvasive squamous cell lung cancer. / Pennycuick, Adam; Teixeira, Vitor H.; Abduljabbar, Khalid; Ahmed Raza, Shan E.; Lund, Tom; Akarca, Ayse U.; Rosenthal, Rachel; Kalinke, Lukas; Chandrasekharan, Deepak P.; Pipinikas, Christodoulos P.; Lee-Six, Henry; Hynds, Robert E.; Gowers, Kate H.C.; Henry, Jake Y.; Millar, Fraser R.; Hagos, Yeman B.; Denais, Celine; Falzon, Mary; Moore, David A.; Antoniou, Sophia; Durrenberger, Pascal F.; Furness, Andrew J.; Carroll, Bernadette; Marceaux, Claire; Asselin-Labat, Marie Liesse; Larson, William; Betts, Courtney; Coussens, Lisa M.; Thakrar, Ricky M.; George, Jeremy; Swanton, Charles; Thirlwell, Christina; Campbell, Peter J.; Marafioti, Teresa; Yuan, Yinyin; Quezada, Sergio A.; McGranahan, Nicholas; Janes, Sam M.
In: Cancer discovery, Vol. 10, No. 10, 10.2020, p. 1489-1499.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Immune surveillance in clinical regression of preinvasive squamous cell lung cancer
AU - Pennycuick, Adam
AU - Teixeira, Vitor H.
AU - Abduljabbar, Khalid
AU - Ahmed Raza, Shan E.
AU - Lund, Tom
AU - Akarca, Ayse U.
AU - Rosenthal, Rachel
AU - Kalinke, Lukas
AU - Chandrasekharan, Deepak P.
AU - Pipinikas, Christodoulos P.
AU - Lee-Six, Henry
AU - Hynds, Robert E.
AU - Gowers, Kate H.C.
AU - Henry, Jake Y.
AU - Millar, Fraser R.
AU - Hagos, Yeman B.
AU - Denais, Celine
AU - Falzon, Mary
AU - Moore, David A.
AU - Antoniou, Sophia
AU - Durrenberger, Pascal F.
AU - Furness, Andrew J.
AU - Carroll, Bernadette
AU - Marceaux, Claire
AU - Asselin-Labat, Marie Liesse
AU - Larson, William
AU - Betts, Courtney
AU - Coussens, Lisa M.
AU - Thakrar, Ricky M.
AU - George, Jeremy
AU - Swanton, Charles
AU - Thirlwell, Christina
AU - Campbell, Peter J.
AU - Marafioti, Teresa
AU - Yuan, Yinyin
AU - Quezada, Sergio A.
AU - McGranahan, Nicholas
AU - Janes, Sam M.
N1 - Funding Information: A. Pennycuick reports grants from Wellcome Trust (salary is funded by the Wellcome Trust clinical PhD programme; Wellcome Trust had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript) during the conduct of the study; in addition, A. Pennycuick has a patent for United Kingdom Patent application no. 1819452.2 pending (covers gene expression and methylation markers of cancer progression in squamous disease). V.H. Teixeira reports a patent for United Kingdom patent application no. 1819452.2 pending (covers gene expression and methylation markers of cancer progression in squamous disease). R. Rosenthal reports personal fees from Achilles Therapeutics outside the submitted work. C.P. Pipinikas reports a patent for United Kingdom patent application no. 1819452.2 pending (covers gene expression and methylation markers of cancer progression in squamous disease). D.A. Moore reports personal fees from AstraZeneca (speaker’s fees) outside the submitted work. A.J.S. Furness reports personal fees from Bristol-Myers Squibb (speaker fees) and personal fees from Ipsen (speaker’s fees) outside the submitted work. C. Marceaux reports grants from NHMRC and other from Viertel Foundation (charitable foundation) during the conduct of the study. M.-L. Asselin-Labat reports grants from NHMRC, other from Viertel Foundation (charitable foundation), and other from Cancer Early Detection and Advanced Research Center at OHSU (philanthropy) during the conduct of the study. L.M. Coussens reports grants from Brenden-Colsson Center for Pancreatic Care; AACR-SU2C during the conduct of the study; Syn-dax Pharmaceuticals (sponsored research), Innate Pharma (sponsored research), Prospect Creek Foundation (sponsored research), Lustgarten Foundation for Pancreatic Cancer Research (sponsored research); nonfinancial support from Cell Signaling Technology (reagent support), Syndax Pharmaceuticals, Inc. (reagent support), Deciphera Pharmaceuticals, LLC (reagent support), Pharmacyclics, Inc [steering committee for PCYC-1137-CA (NCT02436668); advisory board (unpaid)]; personal fees and nonfinancial support from Syndax Pharmaceuticals Inc. (advisory board), Carisma Therapeutics, Inc. (scientific advisory board), Verseau Therapeutics, Inc. (scientific advisory board), Zymeworks, Inc (scientific advisory board), CytomX Therapeutics, Inc. (scientific advisory board), Kineta, Inc. (scientific advisory board), (P30) Koch Institute for Integrated Cancer Research, Massachusetts Institute of Technology [advisory board (academic)], Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins [advisory board (academic)], (P30) Salk Institute Cancer Center [advisory board (academic)], Dana Farber Cancer Center Breast SPORE [advisory board (academic)], (P30) Dana-Farber/Harvard Cancer Center [advisory board (academic)], (P30) University of California, San Diego Moores Cancer Center [advisory board (academic)]; nonfinancial support from Cancer Research Institute (CRI) [advisory board (philanthropic)], The V Foundation for Cancer Research [advisory board (philanthropic)]; Starr Cancer Consortium [advisory board (philanthropic)], Lustgarten Foundation for Pancreatic Cancer Research, Therapeutics Working Group [advisory board (philanthropic)], NIH/NCI-Frederick National Laboratory Advisory Committee (FNLAC) [advisory board (federal government)], Cell Signaling Technology (consultant), Susan G. Komen Foundation, Komen Scholar (consultant); personal fees from AbbVie Inc (consultant), Shasqi, Inc. (consultant), other from AACR: Senior Editor, Cancer Immunology Research (journal); other from AACR: Scientific Editor, Cancer Discovery (journal), and Editorial Board member, Cancer Cell (2014 – present; journal) outside the submitted work. C. Swanton acknowledges grant support from Pfizer, AstraZeneca, Bristol-Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx Inc (collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. C. Swanton holds European patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/ EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/ GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a U.S. patent relating to detecting tumor mutations (PCT/US2017/28013) and both a European and U.S. patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). C. Thirlwell reports personal fees from Ipsen (honoraria), Boehringer-Ingelheim (consulting), and Novartis (conference travel support) outside the submitted work. P.J. Campbell reports grants from Wellcome Trust during the conduct of the study. N. McGranahan reports personal fees from Achilles Therapeutics outside the submitted work; in addition, N. McGranahan has patents 20200000904, 20200000903, and 20180251553 issued. S.M. Janes reports grants from Wellcome Trust, Rosetrees Trust, Welton Trust, Garfield Weston Trust, Stoneygate Trust, UCLH Charitable Foundation, and Stand Up To Cancer during the conduct of the study; grants and personal fees from AstraZeneca [paid advisory board, assistance for travel to meetings (ATS 2018 Takeda WCLC 2019)]; personal fees from Bard1 Bioscience (paid advisory board); personal fees from Achilles Therapeutics (paid advisory board); grants and personal fees from Janssen (paid advisory board, grant income investigator lead); and grants from GRAIL Inc. (grant income investigator lead) and Owlstone (grant income investigator lead) outside the submitted work; in addition, S.M. Janes has a patent for United Kingdom Patent application no. 1819452.2 pending (covers gene expression and methylation markers of cancer progression in squamous disease); and his wife works as a physician for AstraZeneca. No potential conflicts of interest were disclosed by the other authors. Funding Information: We thank all of the patients who participated in this study. We thank P. Rabbitts, A. Banerjee, and C. Read for their early development of the study. The results published here are in part based on data generated by a TCGA pilot project established by the NCI and National Human Genome Research Institute. Information about TCGA and the investiga-tors and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov. R.E. Hynds, N. McGranahan, P.J. Campbell, and S.M. Janes are supported by Wellcome Trust fellowships. S.M. Janes is also supported by the Rosetrees Trust, the Welton Trust, the Garfield Weston Trust, the Stoneygate Trust and UCLH Charitable Foundation, as well as Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Cancer Research Grant (grant number: SU2C-AACR-DT23-17). Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation. The research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C. V.H. Teixeira, C.P. Pipinikas, R.E. Hynds, and S.M. Janes have been funded by the Roy Castle Lung Cancer Foundation. A. Pennycuick and D.P. Chandrasekharan are funded by Wellcome Trust clinical PhD training fellowships. H. Lee-Six is funded by the Wellcome Trust Sanger Institute nonclinical PhD studentship. C. Thirlwell was a CRUK Clinician Scientist. This work was partially undertaken at UCLH/UCL, who received a propor-tion of funding from the Department of Health?s NIHR Biomedical Research Centre?s funding scheme (to S.M. Janes). R.E. Hynds, D.A. Moore, N. McGranahan, C. Swanton, and S.M. Janes are part of the CRUK Lung Cancer Centre of Excellence. C. Swanton is Royal Society Napier Research Professor. His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C. Swanton is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorship Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre 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 (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. C. Swanton also 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 (835297), and Chromavision from the European Union?s Horizon 2020 research and innovation programme (665233). Y. Yuan acknowledges funding from Cancer Research UK Career Establishment Award, Breast Cancer, Children?s Cancer and Leukaemia Group, NIH U54 CA217376 and R01 CA185138, CDMRP Breast Cancer Research Program Award, CRUK Brain Cancer Award (TARGET-GBM), European Commission ITN, Wellcome Trust, and The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. S.A. Quezada is funded by a CRUK Senior Cancer Research Fellowship, a CRUK Biotherapeutic Program Grant, the Cancer Immunotherapy Accelerator Award (CITA-CRUK), and the Rosetrees Trust. L.M. Coussens acknowledges funding from the NIH (1U01 CA224012, U2C CA233280, R01 CA223150, R01, R01 CA226909, R21 HD099367), the Knight Cancer Institute, and the Brenden-Colson Center for Pancreatic Care at OHSU. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: We thank all of the patients who participated in this study. We thank P. Rabbitts, A. Banerjee, and C. Read for their early development of the study. The results published here are in part based on data generated by a TCGA pilot project established by the NCI and National Human Genome Research Institute. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov. R.E. Hynds, N. McGranahan, P.J. Campbell, and S.M. Janes are supported by Wellcome Trust fellowships. S.M. Janes is also supported by the Rosetrees Trust, the Welton Trust, the Garfield Weston Trust, the Stoneygate Trust and UCLH Charitable Foundation, as well as Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Cancer Research Grant (grant number: SU2C-AACR-DT23-17). Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation. The research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C. V.H. Teixeira, C.P. Pipinikas, R.E. Hynds, and S.M. Janes have been funded by the Roy Castle Lung Cancer Foundation. A. Pennycuick and D.P. Chandrasekharan are funded by Wellcome Trust clinical PhD training fellowships. H. Lee-Six is funded by the Wellcome Trust Sanger Institute nonclinical PhD studentship. C. Thirlwell was a CRUK Clinician Scientist. This work was partially undertaken at UCLH/UCL, who received a proportion of funding from the Department of Health’s NIHR Biomedical Research Centre’s funding scheme (to S.M. Janes). R.E. Hynds, D.A. Moore, N. McGranahan, C. Swanton, and S.M. Janes are part of the CRUK Lung Cancer Centre of Excellence. C. Swanton is Royal Society Napier Research Professor. His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C. Swanton is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorship Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Centre, Experimental Cancer Medicine Centre 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 (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. C. Swanton also 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 (835297), and Chromavision from the European Union’s Horizon 2020 research and innovation programme (665233). Y. Yuan acknowledges funding from Cancer Research UK Career Establishment Award, Breast Cancer, Children’s Cancer and Leukaemia Group, NIH U54 CA217376 and R01 CA185138, CDMRP Breast Cancer Research Program Award, CRUK Brain Cancer Award (TARGET-GBM), European Commission ITN, Wellcome Trust, and The Royal Marsden/ICR National Institute of Health Research Biomedical Research Centre. S.A. Quezada is funded by a CRUK Senior Cancer Research Fellowship, a CRUK Biotherapeutic Program Grant, the Cancer Immunotherapy Accelerator Award (CITA-CRUK), and the Rosetrees Trust. L.M. Coussens acknowledges funding from the NIH (1U01 CA224012, U2C CA233280, R01 CA223150, R01, R01 CA226909, R21 HD099367), the Knight Cancer Institute, and the Brenden-Colson Center for Pancreatic Care at OHSU. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2020 American Association for Cancer Research.
PY - 2020/10
Y1 - 2020/10
N2 - Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27–CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGnIFICAnCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcino-genesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.
AB - Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27–CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGnIFICAnCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcino-genesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.
UR - http://www.scopus.com/inward/record.url?scp=85097172451&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097172451&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-19-1366
DO - 10.1158/2159-8290.CD-19-1366
M3 - Article
C2 - 32690541
AN - SCOPUS:85097172451
VL - 10
SP - 1489
EP - 1499
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 10
ER -