{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T14:43:37Z","timestamp":1792507417339,"version":"4.5.0"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T00:00:00Z","timestamp":1613174400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Objective: It has been suggested that the presence of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment is associated with a better prognosis in different types of cancer. In this systematic review and meta-analysis, we investigated the prognostic role of CD4+ and CD8+ TILs in head and neck squamous cell carcinoma (HNSCC). Methods: PubMed, Cochrane, Embase, Scopus, and Web of Science were searched up to September 2020. This study was conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) checklist. Risk ratios from individual studies were displayed in forest plots and the pooled hazard ratios (HR) of death and corresponding confidence intervals (CI) were calculated according to random-effects models. Risk of bias of the included studies was assessed through the Newcastle\u2013Ottawa scale. Results: 28 studies met the inclusion criteria. Studies conducted on HNSCC subsites combined reported a significant reduction in the risk of death for both high CD4+ (HR: 0.77; 95% CI: 0.65\u20130.93) and high CD8+ TILs (HR: 0.64; 95% CI: 0.47\u20130.88). High CD4+ TILs were associated with significantly better overall survival among oropharyngeal HNSCC (HR: 0.52; 95% CI: 0.31\u20130.89), as well as high CD8+ TILS in Human papillomavirus \u2212ve and +ve cancers (HR: 0.39; 95% CI: 0.16\u20130.93 and HR: 0.40; 95% CI 0.21\u20130.76 respectively). CD8+ TILs were also associated with improved survival in hypopharyngeal cancers (HR = 0.43 CI: 0.30\u20130.63). No significant association emerged for patients with cancer of the oral cavity or larynx. Conclusions: The findings from this meta-analysis demonstrate the prognostic significance of CD8+ and CD4+ TILs in HNSCC and variation in tumor subsite warrants further focused investigation. We highlight how TILs may serve as predictive biomarkers to risk stratify patients into treatment groups, with applications in immune-checkpoint inhibitors notable areas for further research.<\/jats:p>","DOI":"10.3390\/cancers13040781","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T02:08:12Z","timestamp":1613268492000},"page":"781","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":115,"title":["Prognostic Significance of CD4+ and CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis"],"prefix":"10.3390","volume":"13","author":[{"given":"Daniele","family":"Borsetto","sequence":"first","affiliation":[{"name":"Department of ENT, Addenbrookes\u2019 Hospital, Cambridge University Hospital Trust, Cambridge CB2 0QQ, UK"},{"name":"Department of Neuroscience, University of Cambridge, Cambridge CB2 1TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1298-1654","authenticated-orcid":false,"given":"Michele","family":"Tomasoni","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology-Head and Neck Surgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Payne","sequence":"additional","affiliation":[{"name":"Institute of Head and Neck Studies and Education, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9381-1520","authenticated-orcid":false,"given":"Jerry","family":"Polesel","sequence":"additional","affiliation":[{"name":"Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1008-7333","authenticated-orcid":false,"given":"Alberto","family":"Deganello","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology-Head and Neck Surgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0135-0224","authenticated-orcid":false,"given":"Paolo","family":"Bossi","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Department of Medical Oncology, ASST Spedali Civili di Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Tysome","sequence":"additional","affiliation":[{"name":"Department of ENT, Addenbrookes\u2019 Hospital, Cambridge University Hospital Trust, Cambridge CB2 0QQ, UK"},{"name":"Department of Neuroscience, University of Cambridge, Cambridge CB2 1TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7214-030X","authenticated-orcid":false,"given":"Liam","family":"Masterson","sequence":"additional","affiliation":[{"name":"Department of ENT, Addenbrookes\u2019 Hospital, Cambridge University Hospital Trust, Cambridge CB2 0QQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Tirelli","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5999-7883","authenticated-orcid":false,"given":"Margherita","family":"Tofanelli","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4635-7959","authenticated-orcid":false,"given":"Paolo","family":"Boscolo-Rizzo","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1016\/j.ejca.2015.07.043","article-title":"Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study","volume":"51","author":"Gatta","year":"2015","journal-title":"Eur. 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