{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T22:47:54Z","timestamp":1792277274730,"version":"4.4.0"},"reference-count":43,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundaci\u00f3n AECC","award":["CICPF16008HERM"],"award-info":[{"award-number":["CICPF16008HERM"]}]},{"name":"Ayudas a Grupos PCTI Principado de Asturias","award":["IDI2018\/155"],"award-info":[{"award-number":["IDI2018\/155"]}]},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Cancer","award":["CB16\/12\/00390"],"award-info":[{"award-number":["CB16\/12\/00390"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sinonasal squamous cell carcinoma (SNSCC) is an aggressive tumor predominantly arising in the maxillary sinus and nasal cavities. Advances in imaging, surgical and radiotherapeutic techniques have reduced complications and morbidity; however, the prognosis generally remains poor, with an overall 5-year survival rate of 30\u201350%. As immunotherapy may be a new therapeutic option, we analyzed CD8+ tumor-infiltrating lymphocytes (TILs) and the tumor microenvironment immune type (TMIT, combining CD8+ TILs and PD-L1) in a series of 57 SNSCCs. Using immunohistochemistry, tissue samples of 57 SNSCCs were analyzed for expression of CD8 on TILs and of PD-L1 on tumor cells. The results were correlated to the clinical and survival data. In total, 88% (50\/57) of the tumors had intratumoral CD8+ TILs; 19% (11\/57)\u2014CD8high (&gt;10%); and 39\/57 (68%)\u2014CD8low (1\u201310%). PD-L1 positivity (&gt;5%) was observed in 46% (26\/57) of the SNSCCs and significantly co-occurred with CD8+ TILs (p = 0.000). Using univariate analysis, high intratumoral CD8+ TILs and TMIT I (CD8high\/PD-L1pos) correlated with a worse survival rate. These results indicate that SNSCCs are immunogenic tumors, similar to head and neck squamous cell carcinomas. Nineteen percent of the cases were both CD8high and PD-L1pos and this subgroup may benefit from therapy with immune checkpoint inhibitors.<\/jats:p>","DOI":"10.3390\/ijms22136926","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T11:45:40Z","timestamp":1624880740000},"page":"6926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Prognostic and Therapeutic Implications of Immune Classification by CD8+ Tumor-Infiltrating Lymphocytes and PD-L1 Expression in Sinonasal Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0331-2002","authenticated-orcid":false,"given":"Roc\u00edo","family":"Garc\u00eda-Mar\u00edn","sequence":"first","affiliation":[{"name":"Department Head and Neck Oncology, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9150-3249","authenticated-orcid":false,"given":"Sara","family":"Reda","sequence":"additional","affiliation":[{"name":"Department Otolaryngology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Riobello","sequence":"additional","affiliation":[{"name":"Department Head and Neck Oncology, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia N.","family":"Cabal","sequence":"additional","affiliation":[{"name":"Department Head and Neck Oncology, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Su\u00e1rez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Department Head and Neck Oncology, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"Vivanco","sequence":"additional","affiliation":[{"name":"Department Pathology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9sar","family":"\u00c1lvarez-Marcos","sequence":"additional","affiliation":[{"name":"Department Otolaryngology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7019-9746","authenticated-orcid":false,"given":"Fernando","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Department Otolaryngology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 L.","family":"Llorente","sequence":"additional","affiliation":[{"name":"Department Otolaryngology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario A.","family":"Hermsen","sequence":"additional","affiliation":[{"name":"Department Head and Neck Oncology, Instituto de Investigaci\u00f3n Sanitaria del Principado de Asturias, 33011 Oviedo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12105-016-0686-9","article-title":"Radiologic Features of Sinonasal Tumors","volume":"10","author":"Koeller","year":"2016","journal-title":"Head Neck Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.canep.2013.09.014","article-title":"International comparisons of the incidence and mortality of sinonasal cancer","volume":"37","author":"Youlden","year":"2013","journal-title":"Cancer Epidemiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1002\/hed.21830","article-title":"Incidence and survival in patients with sinonasal cancer: A historical analysis of population-based data","volume":"34","author":"Turner","year":"2012","journal-title":"Head Neck"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.ctrv.2015.07.004","article-title":"The role of systemic therapy in the management of sinonasal cancer: A critical review","volume":"41","author":"Bossi","year":"2015","journal-title":"Cancer Treat. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/nrclinonc.2014.97","article-title":"Sinonasal carcinoma: Clinical, pathological, genetic and therapeutic advances","volume":"11","author":"Llorente","year":"2014","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.pharmthera.2018.09.008","article-title":"Targeting Programmed Cell Death -1 (PD-1) and Ligand (PD-L1): A new era in cancer active immunotherapy","volume":"194","author":"Constantinidou","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nrc3239","article-title":"The blockade of immune checkpoints in cancer immunotherapy","volume":"12","author":"Pardoll","year":"2012","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3892\/ol.2017.6144","article-title":"Predictive and prognostic significance of CD8+ tumor-infiltrating lymphocytes in patients with luminal B\/HER 2 negative breast cancer treated with neoadjuvant chemotherapy","volume":"14","author":"Ali","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3838","DOI":"10.1200\/JCO.2016.68.1478","article-title":"Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients with Recurrent and\/or Metastatic Head and Neck Squamous Cell Carcinoma: Results from the Phase Ib KEYNOTE-012 Expansion Cohort","volume":"34","author":"Chow","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"104460","DOI":"10.1016\/j.oraloncology.2019.104460","article-title":"Immunotherapy for head and neck cancer: Recent advances and future directions","volume":"99","author":"Cramer","year":"2019","journal-title":"Oral Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1186\/s40425-019-0578-0","article-title":"Comparative analysis of the phase III clinical trials of anti-PD1 monotherapy in head and neck squamous cell carcinoma patients (CheckMate 141 and KEYNOTE 040)","volume":"7","author":"Pai","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nature14011","article-title":"Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients","volume":"515","author":"Herbst","year":"2014","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"328rv4","DOI":"10.1126\/scitranslmed.aad7118","article-title":"PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations","volume":"8","author":"Zou","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1002\/hed.25067","article-title":"Programmed death ligand-1 expression as immunotherapeutic target in sinonasal cancer","volume":"40","author":"Riobello","year":"2018","journal-title":"Head Neck"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4335","DOI":"10.2147\/CMAR.S201568","article-title":"Clinical relevance and significance of programmed death-ligand 1 expression, tumor-infiltrating lymphocytes, and p16 status in sinonasal squamous cell carcinoma","volume":"11","author":"Quan","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/bjc.2013.640","article-title":"Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer","volume":"110","author":"Balermpas","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/bjc.2013.639","article-title":"Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer","volume":"110","author":"Ward","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1158\/1078-0432.CCR-15-1543","article-title":"Evaluation of PD-L1 Expression and Associated Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma","volume":"22","author":"Vassilakopoulou","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-017-3317-2","article-title":"Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma","volume":"17","author":"Fang","year":"2017","journal-title":"BMC Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s00262-020-02479-x","article-title":"The repertoire of tumor-infiltrating lymphocytes within the microenvironment of oral squamous cell carcinoma reveals immune dysfunction","volume":"69","author":"Quan","year":"2020","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_21","first-page":"S022","article-title":"Evaluation of the Immune Microenvironment in Sinonasal Squamous Cell Carcinoma and Its Association with Patients\u2019 Survival","volume":"82","author":"Takahashi","year":"2021","journal-title":"J. Neurol. Surg. Part B Skull Base"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/his.13954","article-title":"Evaluating the prognostic potential of the Ki67 proliferation index and tumour-infiltrating lymphocytes in olfactory neuroblastoma","volume":"75","author":"Classe","year":"2019","journal-title":"Histopathology"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Mar\u00edn, R., Reda, S., Riobello, C., Cabal, V.N., Su\u00e1rez-Fern\u00e1ndez, L., Vivanco, B., L\u00f3pez, F., Llorente, J.L., and Hermsen, M.A. (2020). CD8+ Tumour-Infiltrating Lymphocytes and Tumour Microenvironment Immune Types as Biomarkers for Immunotherapy in Sinonasal Intestinal-Type Adenocarcinoma. Vaccines, 8.","DOI":"10.3390\/vaccines8020202"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"127ra37","DOI":"10.1126\/scitranslmed.3003689","article-title":"Colocalization of Inflammatory Response with B7-H1 Expression in Human Melanocytic Lesions Supports an Adaptive Resistance Mechanism of Immune Escape","volume":"4","author":"Taube","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1158\/1078-0432.CCR-15-2834","article-title":"Pan-Cancer Immunogenomic Perspective on the Tumor Microenvironment Based on PD-L1 and CD8 T-Cell Infiltration","volume":"22","author":"Ock","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2139","DOI":"10.1158\/0008-5472.CAN-15-0255","article-title":"Classifying Cancers Based on T-cell Infiltration and PD-L1","volume":"75","author":"Teng","year":"2015","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1126\/science.aaf2834","article-title":"The \u201ccancer immunogram\u201d","volume":"352","author":"Blank","year":"2016","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e187","DOI":"10.1016\/j.wneu.2019.11.112","article-title":"Expression of Programmed Cell Death Ligand 1 and Associated Lymphocyte Infiltration in Olfactory Neuroblastoma","volume":"135","author":"London","year":"2020","journal-title":"World Neurosurg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"18538","DOI":"10.1073\/pnas.0509182102","article-title":"Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+\/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer","volume":"102","author":"Sato","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","first-page":"5132","article-title":"Proliferative activity of intratumoural CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: Clinicopathologic demonstration of antitumour immunity","volume":"61","author":"Nakano","year":"2001","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1002\/cncr.23712","article-title":"Predominant infiltration of macrophages and CD8+T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer","volume":"113","author":"Kawai","year":"2008","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e26","DOI":"10.1097\/00006676-200401000-00023","article-title":"CD8+ Tumor-Infiltrating Lymphocytes Together with CD4+ Tumor-Infiltrating Lymphocytes and Dendritic Cells Improve the Prognosis of Patients with Pancreatic Adenocarcinoma","volume":"28","author":"Fukunaga","year":"2004","journal-title":"Pancreas"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1111\/j.1349-7006.2003.tb01392.x","article-title":"CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers","volume":"94","author":"Wakabayashi","year":"2003","journal-title":"Cancer Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1159\/000325986","article-title":"Clinicopathologic Roles of Tumor-Infiltrating Lymphocytes and CD8-Positive Lymphocytes in Lung Cancer Imprint Smears in Squamous Cell Carcinoma and Adenocarcinoma","volume":"50","author":"Ikeda","year":"2006","journal-title":"Acta Cytol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ejca.2017.08.026","article-title":"Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma","volume":"86","author":"Kinoshita","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.coi.2018.03.006","article-title":"The transition from HLA-I positive to HLA-I negative primary tumors: The road to escape from T-cell responses","volume":"51","author":"Aptsiauri","year":"2018","journal-title":"Curr. Opin. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Wickenhauser, C., Bethmann, D., Kappler, M., Eckert, A.W., Steven, A., Bukur, J., Fox, B.A., Beer, J., and Seliger, B. (2021). Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma. Cancers, 13.","DOI":"10.20944\/preprints202101.0179.v1"},{"key":"ref_39","first-page":"368","article-title":"EGFR mutation and HPV infection in sinonasal inverted papilloma and squamous cell carcinoma","volume":"58","author":"Cabal","year":"2020","journal-title":"Rhinol. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1111\/apm.12003","article-title":"Detection of human papillomavirus in esophageal papillomas: Systematic review and meta-analysis","volume":"121","year":"2013","journal-title":"APMIS"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1093\/annonc\/mdx736","article-title":"Human papillomavirus (HPV) and somatic EGFR mutations are essential, mutually exclusive oncogenic mechanisms for inverted sinonasal papillomas and associated sinonasal squamous cell carcinomas","volume":"29","author":"Udager","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/ijc.31971","article-title":"Comprehensive analysis of HPV infection, EGFR exon 20 mutations and LINE1 hypomethylation as risk factors for malignant transformation of sinonasal-inverted papilloma to squamous cell carcinoma","volume":"144","author":"Sahnane","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1016\/S1470-2045(16)30066-3","article-title":"Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): An open-label, multicentre, phase 1b trial","volume":"17","author":"Seiwert","year":"2016","journal-title":"Lancet Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6926\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:35Z","timestamp":1760163935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,28]]},"references-count":43,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136926"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136926","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,28]]}}}