{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T16:00:38Z","timestamp":1777564838191,"version":"3.51.4"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:00:00Z","timestamp":1735862400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:00:00Z","timestamp":1735862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SCHU 25639-1"],"award-info":[{"award-number":["SCHU 25639-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BR 289111-1"],"award-info":[{"award-number":["BR 289111-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Universit\u00e4tsklinikum Ulm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide with a poor prognosis for survival. Risk factors include alcohol and tobacco abuse and infection with human papilloma virus (HPV). To enhance anti-tumor immune responses immunotherapeutic approaches are approved for recurrent metastatic disease but only approx. 20% of patients respond to checkpoint blockade of the PD-1\/PD-L1 axis. Therefore, preclinical research is needed to better understand molecular and cellular processes and to identify new therapeutic targets. Immunocompetent mouse models can serve these purposes but only few are currently available for HPV-positive HNSCC. Here, we established a mouse cell line overexpressing the oncogenes <jats:italic>E6<\/jats:italic>\/<jats:italic>E7<\/jats:italic> of the HPV16 genome as well as a constitutively active form of H-Ras and studied the anti-tumor immune response upon orthotopic tumor growth at the floor of the mouth. Moreover, we analyzed the same immunoregulatory pathways in samples of HPV-positive cancer patients. T cells in the tumor of mice and humans exhibited high expression of CD39 and CD73, two ectoenzymes involved in the production of immunosuppressive adenosine from ATP, along with increased expression of PD-1, LAG-3 and GITR. Additionally, B cell responses were elevated in tumor-bearing mice, seen as an increase of germinal center, immunoregulatory marginal zone and follicular B cell subtypes. Taken together, this study suggests that the generated mouse model shares characteristics with human disease and can thus be used as a platform to study anti-tumor responses in HPV-positive HNSCC which will help to identify novel therapeutic targets.<\/jats:p>","DOI":"10.1007\/s00262-024-03907-y","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T10:05:40Z","timestamp":1735898740000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Characterization of the adaptive immune response in a mouse model for HPV-positive head and neck squamous cell carcinoma with implications to human disease"],"prefix":"10.1007","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-448X","authenticated-orcid":false,"given":"Franziska","family":"Oliveri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Neher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7184-8453","authenticated-orcid":false,"given":"Ronja","family":"Pscheid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabel","family":"Sewald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sowmya","family":"Gowdavally","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3261-7008","authenticated-orcid":false,"given":"Annika C.","family":"Betzler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaqueline","family":"Hallitsch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0628-0608","authenticated-orcid":false,"given":"Jens","family":"Greve","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Laban","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1232-5350","authenticated-orcid":false,"given":"Sebastian","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5127-3779","authenticated-orcid":false,"given":"Thomas K.","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1065-8709","authenticated-orcid":false,"given":"Patrick J.","family":"Schuler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6456-5508","authenticated-orcid":false,"given":"Cornelia","family":"Brunner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,1,3]]},"reference":[{"key":"3907_CR1","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/s41571-022-00603-7","volume":"19","author":"M Lechner","year":"2022","unstructured":"Lechner M, Liu J, Masterson L, Fenton TR (2022) HPV-associated oropharyngeal cancer: epidemiology, molecular biology and clinical management. Nat Rev Clin Oncol 19:306\u2013327. https:\/\/doi.org\/10.1038\/s41571-022-00603-7","journal-title":"Nat Rev Clin Oncol"},{"key":"3907_CR2","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1093\/jnci\/djn025","volume":"100","author":"ML Gillison","year":"2008","unstructured":"Gillison ML, D\u2019Souza G, Westra W et al (2008) Distinct risk factor profiles for human papillomavirus type 16\u2013positive and human papillomavirus type 16\u2013negative head and neck cancers. JNCI J Nat Cancer Inst 100:407\u2013420. https:\/\/doi.org\/10.1093\/jnci\/djn025","journal-title":"JNCI J Nation Cancer Inst"},{"key":"3907_CR3","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1038\/nature14129","volume":"517","author":"MS Lawrence","year":"2015","unstructured":"Lawrence MS, Sougnez C, Lichtenstein L et al (2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517:576\u2013582. https:\/\/doi.org\/10.1038\/nature14129","journal-title":"Nature"},{"key":"3907_CR4","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","volume":"6","author":"DE Johnson","year":"2020","unstructured":"Johnson DE, Burtness B, Leemans CR et al (2020) Head and neck squamous cell carcinoma. Nat Rev Dis Primers 6:92. https:\/\/doi.org\/10.1038\/s41572-020-00224-3","journal-title":"Nat Rev Dis Primers"},{"issue":"3293","key":"3907_CR5","doi-asserted-by":"publisher","first-page":"3304","DOI":"10.1200\/JCO.2015.61.1509","volume":"33","author":"RL Ferris","year":"2015","unstructured":"Ferris RL (2015) Immunology and immunotherapy of head and neck cancer. J Clin Oncol 33(3293):3304. https:\/\/doi.org\/10.1200\/JCO.2015.61.1509","journal-title":"J Clin Oncol"},{"key":"3907_CR6","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/S0140-6736(19)32591-7","volume":"394","author":"B Burtness","year":"2019","unstructured":"Burtness B, Harrington KJ, Greil R et al (2019) Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. The Lancet 394:1915\u20131928. https:\/\/doi.org\/10.1016\/S0140-6736(19)32591-7","journal-title":"The Lancet"},{"key":"3907_CR7","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1001\/archotol.133.5.495","volume":"133","author":"AC Hoover","year":"2007","unstructured":"Hoover AC, Spanos WC, Harris GF et al (2007) The role of human papillomavirus 16 E6 in anchorage-independent and invasive growth of mouse tonsil epithelium. Arch Otolaryngol Head Neck Surg 133:495\u2013502. https:\/\/doi.org\/10.1001\/archotol.133.5.495","journal-title":"Arch Otolaryngol Head Neck Surg"},{"key":"3907_CR8","doi-asserted-by":"crossref","unstructured":"Shivarudrappa AH, John J, Vashisht M, et al (2024) Differential tumor immune microenvironment coupled with tumor progression or tumor eradication in HPV-antigen expressing squamous cell carcinoma (SCC) models. Front Immunol 15:","DOI":"10.3389\/fimmu.2024.1405318"},{"key":"3907_CR9","doi-asserted-by":"publisher","unstructured":"Leichtle F, Betzler AC, Eizenberger C, et al (2023) Influence of Bruton\u2019s Tyrosine Kinase (BTK) on epithelial\u2013mesenchymal transition (EMT) processes and cancer stem cell (CSC) enrichment in head and neck squamous cell carcinoma (HNSCC). 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Nat Rev Cancer 23:173\u2013188. https:\/\/doi.org\/10.1038\/s41568-022-00531-9","journal-title":"Nat Rev Cancer"},{"key":"3907_CR12","doi-asserted-by":"publisher","unstructured":"Lechner A, Schl\u00f6\u00dfer H, Rothschild SI, et al (2017) Characterization of tumor-associated T-lymphocyte subsets and immune checkpoint molecules in head and neck squamous cell carcinoma. Oncotarget 8:44418\u201344433. https:\/\/doi.org\/10.18632\/oncotarget.17901","DOI":"10.18632\/oncotarget.17901"},{"key":"3907_CR13","doi-asserted-by":"crossref","unstructured":"Damasio MPS, Nascimento CS, Andrade LM, et al (2022) The role of T-cells in head and neck squamous cell carcinoma: From immunity to immunotherapy. 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Br J Cancer 109:2629\u20132635. https:\/\/doi.org\/10.1038\/bjc.2013.645","journal-title":"Br J Cancer"},{"key":"3907_CR20","doi-asserted-by":"publisher","first-page":"3349","DOI":"10.1038\/s41467-021-23355-x","volume":"12","author":"AT Ruffin","year":"2021","unstructured":"Ruffin AT, Cillo AR, Tabib T et al (2021) B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma. Nat Commun 12:3349. https:\/\/doi.org\/10.1038\/s41467-021-23355-x","journal-title":"Nat Commun"}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-024-03907-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-024-03907-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-024-03907-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T01:10:20Z","timestamp":1739149820000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-024-03907-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,3]]},"references-count":20,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["3907"],"URL":"https:\/\/doi.org\/10.1007\/s00262-024-03907-y","relation":{},"ISSN":["1432-0851"],"issn-type":[{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,3]]},"assertion":[{"value":"23 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Ulm University (Votum #90\/15).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"All donors of the present study provided informed and written consent. Animal experimentation was approved by the Regierungspr\u00e4sidium T\u00fcbingen (permission number #1607).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}}],"article-number":"66"}}