{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:48:51Z","timestamp":1786121331555,"version":"build-2736575974"},"reference-count":27,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Despite advances in immune checkpoint inhibitors (ICIs), the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) remains poor, and reliable biomarkers for predicting clinical outcomes are still lacking. CD161, a lectin-like receptor expressed on multiple T-cell subsets, has been reported to inhibit T-cell cytotoxicity; however, its prognostic and immunological significance in HNSCC remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed transcriptomic data from the HNSCC cohort in the TCGA database and four GEO datasets (GSE6631, GSE102349, GSE159067, and GSE103322) to evaluate CD161 expression, its prognostic significance, and its association with immune infiltration and functional pathways. Single-cell RNA sequencing data were used to identify CD161-expressing cell subsets. Differential expression was further validated by immunohistochemistry (IHC) in 20 paired HNSCC and adjacent normal tissues. The association between CD161 expression and immunotherapy response was additionally assessed in an independent cohort of 33 ICI-treated patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CD161 expression was significantly lower in HNSCC tissues than in normal tissues in the TCGA cohort and the GSE6631 dataset, which was further confirmed by IHC analysis. High CD161 expression was associated with a favorable prognosis, with longer overall survival (OS) and disease-specific survival (DSS), and remained an independent protective factor in multivariate analysis (OS: hazard ratio [HR] = 0.92, 95% confidence interval [CI]: 0.86\u20130.99, p = 0.019; DSS: HR\u00a0=\u00a00.86, 95% CI: 0.78\u20130.96, p = 0.008). CD161 expression correlated with infiltration of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and regulatory T cells, as well as with multiple immune checkpoint molecules, including CD27, TIGIT, BTLA, and PD-1. Single-cell analysis further localized CD161 predominantly to CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells. In the GSE159067 dataset, high CD161 expression was associated with longer progression-free survival and overall survival. In our ICI-treated cohort, high CD161 expression correlated with longer PFS and higher objective response rate.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CD161 is downregulated in HNSCC. Higher CD161 expression is associated with favorable prognosis and an immune-inflamed tumor microenvironment, and may predict response to ICI-containing therapy. These findings suggest that CD161 has potential as a prognostic biomarker and may help characterize tumor\u2013immune interactions in HNSCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1855876","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:22:11Z","timestamp":1786076531000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CD161 serves as a prognostic biomarker and predicts immunotherapy response in head and neck squamous cell carcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Shuai","family":"Mei","sequence":"first","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Xuzhou Medical University","place":["Xuzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Oncology, Henan Provincial People\u2019s Hospital, People\u2019s Hospital of Zhengzhou University, People\u2019s Hospital of Henan University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haizhu","family":"Chen","sequence":"additional","affiliation":[{"name":"Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pathology, Suqian Affiliated Hospital of Xuzhou Medical University","place":["Suqian, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine, Bengbu Medical University","place":["Bengbu, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Xuzhou Medical University","place":["Xuzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxia","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Xuzhou Medical University","place":["Xuzhou, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA: A Cancer J For Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/1748-717x-6-70","article-title":"Long-term outcome and patterns of failure in patients with advanced head and neck cancer","volume":"6","author":"Hauswald","year":"2011","journal-title":"Radiat Oncol (London England)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1269863","article-title":"Locally advanced head and neck squamous cell carcinoma treatment efficacy and safety: a systematic review and network meta-analysis","volume":"14","author":"Wang","year":"2023","journal-title":"Front Pharmacol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(19)32591-7","article-title":"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","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet (London England)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1602252","article-title":"Nivolumab for recurrent squamous-cell carcinoma of the head and neck","volume":"375","author":"Ferris","year":"2016","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1093\/annonc\/mdy470","article-title":"Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy","volume":"30","author":"Chen","year":"2019","journal-title":"Ann Oncol Off J Eur Soc For Med Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01835-2","article-title":"Treating head and neck cancer in the age of immunotherapy: a 2023 update","volume":"83","author":"Bhatia","year":"2023","journal-title":"Drugs"},{"key":"B8","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s12943-024-02212-7","article-title":"Resistance mechanisms to immune checkpoint inhibitors: updated insights","volume":"24","author":"Alsaafeen Besan","year":"2025","journal-title":"Mol Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1093\/noajnl\/vdab070.059","article-title":"Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis","volume":"184","author":"Mathewson","year":"2021","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15236","article-title":"Clinical characterization and immunosuppressive regulation of CD161 (KLRB1) in glioma through 916 samples","volume":"113","author":"Di","year":"2022","journal-title":"Cancer Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.cir-22-0356","article-title":"CD8+ T cell-dependent remodeling of the tumor microenvironment overcomes chemoresistance","volume":"11","author":"Lao","year":"2023","journal-title":"Cancer Immunol Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2017.1423184","article-title":"Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome","volume":"7","author":"Braud","year":"2018","journal-title":"Oncoimmunology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.996345","article-title":"Identification of CD161 expression as a novel prognostic biomarker in breast cancer correlated with immune infiltration","volume":"13","author":"Weng","year":"2022","journal-title":"Front Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.21037\/tcr-23-697","article-title":"KLRB1 is a novel prognostic biomarker in endometrial cancer and is associated with immune infiltration","volume":"12","author":"Liang","year":"2023","journal-title":"Trans Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e133103","DOI":"10.1172\/jci.insight.133103","article-title":"Discovery of specialized NK cell populations infiltrating human melanoma metastases","volume":"4","author":"de Andrade","year":"2019","journal-title":"JCI Insight"},{"key":"B16","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1016\/j.cell.2020.11.041","article-title":"Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma","volume":"184","author":"Sun","year":"2021","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1040289","article-title":"A pan-cancer and single-cell sequencing analysis of CD161, a promising onco-immunological biomarker in tumor microenvironment and immunotherapy","volume":"13","author":"Li","year":"2022","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.cir-22-0454","article-title":"CD161 characterizes an inflamed subset of cytotoxic T lymphocytes associated with prolonged survival in human papillomavirus-driven oropharyngeal cancer","volume":"11","author":"Wei","year":"2023","journal-title":"Cancer Immunol Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.688215","article-title":"A pan-cancer analysis of CD161, a potential new immune checkpoint","volume":"12","author":"Zhou","year":"2021","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.847576","article-title":"LLT1-CD161 interaction in cancer: promises and challenges","volume":"13","author":"Braud","year":"2022","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"11782","DOI":"10.1038\/s41598-024-60414-x","article-title":"Down-regulation of KLRB1 is associated with increased cell growth, metastasis, poor prognosis, as well as a dysfunctional immune microenvironment in LUAD","volume":"14","author":"Chen","year":"2024","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00486","article-title":"CD161 defines a functionally distinct subset of pro-inflammatory natural killer cells","volume":"9","author":"Kurioka","year":"2018","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0130-2","article-title":"Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates","volume":"557","author":"Simoni","year":"2018","journal-title":"Nature"},{"key":"B24","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1016\/j.cell.2019.10.003","article-title":"Landscape and dynamics of single immune cells in hepatocellular carcinoma","volume":"179","author":"Zhang","year":"2019","journal-title":"Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nature13988","article-title":"Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens","volume":"515","author":"Gubin","year":"2014","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e003995","DOI":"10.1136\/jitc-2021-003995","article-title":"CD161 expression and regulation defines rapidly responding effector CD4+ T cells associated with improved survival in HPV16-associated tumors","volume":"10","author":"Duurland","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.353","article-title":"Immune checkpoint CD161\/LLT1-associated immunological landscape and diagnostic value in oral squamous cell carcinoma","volume":"10","author":"Hu","year":"2024","journal-title":"J Pathol Clin Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1855876\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:22:11Z","timestamp":1786076531000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1855876\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":27,"alternative-id":["10.3389\/fimmu.2026.1855876"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1855876","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]},"article-number":"1855876"}}