{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:13:14Z","timestamp":1792800794111,"version":"4.5.0"},"reference-count":30,"publisher":"Rockefeller University Press","issue":"10","license":[{"start":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T00:00:00Z","timestamp":1595808000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T00:00:00Z","timestamp":1617580800000},"content-version":"vor","delay-in-days":252,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016253","name":"Atara Biotherapeutics","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100016253","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,10,5]]},"abstract":"<jats:p>Cellular immunotherapeutics targeting the human papillomavirus (HPV)\u201316 E6 and E7 proteins have achieved limited success in HPV-positive oropharyngeal cancer (OPC). Here we have conducted proteome-wide profiling of HPV-16\u2013specific T cell responses in a cohort of 66 patients with HPV-associated OPC and 22 healthy individuals. Unexpectedly, HPV-specific T cell responses from OPC patients were not constrained to the E6 and E7 antigens; they also recognized E1, E2, E4, E5, and L1 proteins as dominant targets for virus-specific CD8+ and CD4+ T cells. Multivariate analysis incorporating tumor staging, treatment status, and smoking history revealed that treatment status had the most significant impact on HPV-specific CD8+ and CD4+ T cell immunity. Specifically, the breadth and overall strength of HPV-specific T cell responses were significantly higher before the commencement of curative therapy than after therapy. These data provide the first glimpse of the overall human T cell response to HPV in a clinical setting and offer groundbreaking insight into future development of cellular immunotherapies for HPV-associated OPC patients.<\/jats:p>","DOI":"10.1084\/jem.20200389","type":"journal-article","created":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T13:17:02Z","timestamp":1595855822000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":64,"title":["Profiling HPV-16\u2013specific T cell responses reveals broad antigen reactivities in oropharyngeal cancer patients"],"prefix":"10.1084","volume":"217","author":[{"given":"Kunal H.","family":"Bhatt","sequence":"first","affiliation":[{"name":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle A.","family":"Neller","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sriganesh","family":"Srihari","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Crooks","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea","family":"Lekieffre","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4020-2718","authenticated-orcid":true,"given":"Blake T.","family":"Aftab","sequence":"additional","affiliation":[{"name":"Department of Preclinical and Translational Sciences, Atara Biotherapeutics, Thousand Oaks, Los Angeles, CA 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Liu","sequence":"additional","affiliation":[{"name":"Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, Australia 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corey","family":"Smith","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7556-0542","authenticated-orcid":true,"given":"Liz","family":"Kenny","sequence":"additional","affiliation":[{"name":"School of Medicine, The University of Queensland and Royal Brisbane and Women's Hospital, Herston, Queensland, Australia 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0937-6939","authenticated-orcid":true,"given":"Sandro","family":"Porceddu","sequence":"additional","affiliation":[{"name":"Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland, Australia 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2241-0353","authenticated-orcid":true,"given":"Rajiv","family":"Khanna","sequence":"additional","affiliation":[{"name":"QIMR Berghofer Centre for Immunotherapy and Vaccine Development, Tumour Immunology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia 1"},{"name":"School of Medicine, The University of Queensland and Royal Brisbane and Women's Hospital, Herston, Queensland, Australia 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2020,7,27]]},"reference":[{"key":"2025042816332293000_bib1","doi-asserted-by":"publisher","first-page":"11146","DOI":"10.1158\/0008-5472.CAN-05-0772","article-title":"Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck","volume":"65","author":"Albers","year":"2005","journal-title":"Cancer Res"},{"key":"2025042816332293000_bib2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191581","article-title":"Association of an intact E2 gene with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome in HPV16 positive head and neck squamous cell carcinoma","volume":"13","author":"Anayannis","year":"2018","journal-title":"PLoS One"},{"key":"2025042816332293000_bib3","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1016\/j.oraloncology.2015.05.007","article-title":"Biologic predictors of serologic responses to HPV in oropharyngeal cancer: The HOTSPOT study","volume":"51","author":"Anderson","year":"2015","journal-title":"Oral Oncol"},{"key":"2025042816332293000_bib4","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1056\/NEJMoa0912217","article-title":"Human papillomavirus and survival of patients with oropharyngeal cancer","volume":"363","author":"Ang","year":"2010","journal-title":"N. Engl. J. Med"},{"key":"2025042816332293000_bib5","doi-asserted-by":"publisher","first-page":"1755","DOI":"10.1128\/JCM.44.5.1755-1762.2006","article-title":"Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer","volume":"44","author":"Arias-Pulido","year":"2006","journal-title":"J. Clin. Microbiol"},{"key":"2025042816332293000_bib6","doi-asserted-by":"publisher","first-page":"4294","DOI":"10.1200\/JCO.2011.36.4596","article-title":"Human papillomavirus and rising oropharyngeal cancer incidence in the United States","volume":"29","author":"Chaturvedi","year":"2011","journal-title":"J. Clin. Oncol"},{"key":"2025042816332293000_bib7","doi-asserted-by":"publisher","first-page":"4550","DOI":"10.1200\/JCO.2013.50.3870","article-title":"Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers","volume":"31","author":"Chaturvedi","year":"2013","journal-title":"J. Clin. Oncol"},{"key":"2025042816332293000_bib8","doi-asserted-by":"publisher","first-page":"e180","DOI":"10.1016\/S2214-109X(19)30488-7","article-title":"Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis","volume":"8","author":"de Martel","year":"2020","journal-title":"Lancet Glob. Health"},{"key":"2025042816332293000_bib9","doi-asserted-by":"publisher","first-page":"2506","DOI":"10.1002\/lary.27807","article-title":"Long-term survival in head and neck cancer: impact of site, stage, smoking, and human papillomavirus status","volume":"129","author":"Du","year":"2019","journal-title":"Laryngoscope"},{"issue":"8","key":"2025042816332293000_bib10","doi-asserted-by":"publisher","first-page":"S184","DOI":"10.4103\/0973-1482.179190","article-title":"Effect of smoking on high-grade cervical cancer in women on the basis of human papillomavirus infection studies","volume":"14","author":"Fang","year":"2018","journal-title":"J. Cancer Res. Ther"},{"key":"2025042816332293000_bib11","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1099\/0022-1317-79-8-1971","article-title":"Proliferative T-cell responses to human papillomavirus type 16 E5 are decreased amongst women with high-grade neoplasia","volume":"79","author":"Gill","year":"1998","journal-title":"J. Gen. Virol"},{"key":"2025042816332293000_bib12","doi-asserted-by":"publisher","first-page":"3235","DOI":"10.1200\/JCO.2015.61.6995","article-title":"Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma","volume":"33","author":"Gillison","year":"2015","journal-title":"J. Clin. Oncol"},{"key":"2025042816332293000_bib13","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/S0140-6736(18)32779-X","article-title":"Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial","volume":"393","author":"Gillison","year":"2019","journal-title":"Lancet"},{"key":"2025042816332293000_bib14","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.124762","article-title":"Variations in HPV function are associated with survival in squamous cell carcinoma","volume":"4","author":"Gleber-Netto","year":"2019","journal-title":"JCI Insight"},{"key":"2025042816332293000_bib15","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.ejca.2019.10.025","article-title":"Concurrent cisplatin or cetuximab with radiotherapy for HPV-positive oropharyngeal cancer: Medical resource use, costs, and quality-adjusted survival from the De-ESCALaTE HPV trial","volume":"124","author":"Jones","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"2025042816332293000_bib16","doi-asserted-by":"publisher","first-page":"1859","DOI":"10.1002\/cncr.31256","article-title":"Screening for human papillomavirus-driven oropharyngeal cancer: Considerations for feasibility and strategies for research","volume":"124","author":"Kreimer","year":"2018","journal-title":"Cancer"},{"key":"2025042816332293000_bib17","doi-asserted-by":"publisher","first-page":"6159","DOI":"10.1158\/0008-5472.CAN-18-0163","article-title":"Human papilloma virus specific immunogenicity and dysfunction of CD8+ T cells in head and neck cancer","volume":"78","author":"Krishna","year":"2018","journal-title":"Cancer Res"},{"key":"2025042816332293000_bib18","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1016\/j.ejca.2014.07.001","article-title":"De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials","volume":"50","author":"Masterson","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"2025042816332293000_bib19","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.ejca.2016.08.012","article-title":"CD8+ T cell response to human papillomavirus 16 E7 is able to predict survival outcome in oropharyngeal cancer","volume":"67","author":"Masterson","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"2025042816332293000_bib20","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/S0140-6736(18)32752-1","article-title":"Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial","volume":"393","author":"Mehanna","year":"2019","journal-title":"Lancet"},{"key":"2025042816332293000_bib21","doi-asserted-by":"publisher","first-page":"208","DOI":"10.3390\/v9080208","article-title":"Integration of human papillomavirus genomes in head and neck cancer: is it time to consider a paradigm shift?","volume":"9","author":"Morgan","year":"2017","journal-title":"Viruses"},{"key":"2025042816332293000_bib22","first-page":"677","article-title":"Relationship between smoking, HPV infection, and risk of Cervical cancer","volume":"36","author":"Mzarico","year":"2015","journal-title":"Eur. J. Gynaecol. Oncol"},{"key":"2025042816332293000_bib23","doi-asserted-by":"publisher","first-page":"17684","DOI":"10.18632\/oncotarget.15179","article-title":"Analysis of The Cancer Genome Atlas sequencing data reveals novel properties of the human papillomavirus 16 genome in head and neck squamous cell carcinoma","volume":"8","author":"Nulton","year":"2017","journal-title":"Oncotarget"},{"key":"2025042816332293000_bib24","doi-asserted-by":"publisher","first-page":"7205","DOI":"10.1158\/0008-5472.CAN-14-1913","article-title":"Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer","volume":"74","author":"Parikh","year":"2014","journal-title":"Cancer Res"},{"key":"2025042816332293000_bib25","doi-asserted-by":"publisher","DOI":"10.4081\/oncol.2012.e17","article-title":"Mechanisms of virus immune evasion lead to development from chronic inflammation to cancer formation associated with human papillomavirus infection","volume":"6","author":"Senba","year":"2012","journal-title":"Oncol. Rev"},{"key":"2025042816332293000_bib26","doi-asserted-by":"publisher","first-page":"6929","DOI":"10.1158\/1078-0432.CCR-04-0672","article-title":"Effect of human papillomavirus-16 infection on CD8+ T-cell recognition of a wild-type sequence p53264-272 peptide in patients with squamous cell carcinoma of the head and neck","volume":"10","author":"Sirianni","year":"2004","journal-title":"Clin. Cancer Res"},{"key":"2025042816332293000_bib27","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1001\/archoto.2009.159","article-title":"Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer","volume":"135","author":"Spanos","year":"2009","journal-title":"Arch. Otolaryngol. Head Neck Surg"},{"key":"2025042816332293000_bib28","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1267095","article-title":"Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients","volume":"6","author":"van Meir","year":"2016","journal-title":"OncoImmunology"},{"key":"2025042816332293000_bib29","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1001\/archoto.2010.211","article-title":"Correlation of cellular immunity with human papillomavirus 16 status and outcome in patients with advanced oropharyngeal cancer","volume":"136","author":"Wansom","year":"2010","journal-title":"Arch. Otolaryngol. Head Neck Surg"},{"key":"2025042816332293000_bib30","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1080\/14712598.2017.1315100","article-title":"Immunotherapy for head and neck cancer: the future of treatment?","volume":"17","author":"Xie","year":"2017","journal-title":"Expert Opin. Biol. Ther"}],"updated-by":[{"DOI":"10.1084\/jem.2020038910192022c","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000}}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20200389\/1916642\/jem_20200389.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/doi\/10.1084\/jem.20200389\/1916642\/jem_20200389.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T20:33:27Z","timestamp":1745872407000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/217\/10\/e20200389\/151975\/Profiling-HPV-16-specific-T-cell-responses-reveals"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,27]]},"references-count":30,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2020,10,5]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20200389","relation":{"correction":[{"id-type":"doi","id":"10.1084\/jem.2020038910192022c","asserted-by":"object"}]},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,27]]},"article-number":"e20200389"}}