{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T20:55:43Z","timestamp":1789678543060,"version":"4.0.1"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T00:00:00Z","timestamp":1667779200000},"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><jats:title>Background<\/jats:title><jats:p>Thyroid tissue has a special immune microenvironment that is not well characterized. Whether immune cells have a prognostic value in the recurrence of papillary thyroid cancer (PTC) needs further investigation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Multinodular non-toxic goiter (MNG) was taken as normal tissue for the difficulty in obtaining completely normal thyroid tissue (normal thyroid function, no thyroiditis, and no nodules). We compared the composition of mononuclear cells (MNCs) in peripheral blood and thyroid tissues from MNG and PTC patients by high-dimensional flow cytometry profiling and verified the results by multiplex immunohistochemistry. The recurrence rates of PTC patients with different CD8<jats:sup>+<\/jats:sup>T cell subset signatures were compared using TCGA database.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We observed that the immune cell composition of MNG was different from that in peripheral blood. Thyroid tissue contains higher percentages of T cells and NK cells. Moreover, the percentages of memory T cells and Treg cells were higher in thyroid than in peripheral blood and increased in PTC tumors. We further focused on the antitumoral CD8<jats:sup>+<\/jats:sup>T cells and found that the expression patterns of PD-1, CD39, and CD103 on CD8<jats:sup>+<\/jats:sup>T cells were different between MNG and PTC. Importantly, we found higher percentages of PD-1<jats:sup>+<\/jats:sup>CD39<jats:sup>+<\/jats:sup>CD103<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup>T and PD-1<jats:sup>+<\/jats:sup>CD39<jats:sup>+<\/jats:sup>CD103<jats:sup>-<\/jats:sup>CD8<jats:sup>+<\/jats:sup>T cells in PTC tumor tissues from recurrent patients than non-recurrent patients. By analyzing PTC data from TCGA database, we found that the expression patterns of these molecules were associated with different pathologic types and genders among PTC patients. Moreover, patients with PD-1<jats:sup>hi<\/jats:sup>CD39<jats:sup>lo<\/jats:sup>CD103<jats:sup>hi<\/jats:sup>CD8<jats:sup>hi<\/jats:sup>, PD-1<jats:sup>hi<\/jats:sup>CD39<jats:sup>hi<\/jats:sup>CD103<jats:sup>lo<\/jats:sup>CD8<jats:sup>hi<\/jats:sup>, and PD-1<jats:sup>lo<\/jats:sup>CD39<jats:sup>hi<\/jats:sup>CD103<jats:sup>hi<\/jats:sup>CD8<jats:sup>hi<\/jats:sup> expression patterns have a higher 10-year recurrence-free survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The immune microenvironment in MNG tissue is distinct from that in peripheral blood and paratumor tissue. More memory CD8<jats:sup>+<\/jats:sup>T cells were detected in PTC, and expression patterns of PD-1, CD39, and CD103 on CD8<jats:sup>+<\/jats:sup>T cells were significantly different in physiology and gender and associated with the recurrence rate of PTC. These observations indicate that CD8<jats:sup>+<\/jats:sup>T cell signatures may be useful prognostic markers for PTC recurrence.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.894919","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T06:43:16Z","timestamp":1667803396000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Immune profiling identifies CD8+ T-cell subset signatures as prognostic markers for recurrence in papillary thyroid cancer"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhen","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Li","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Yi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing-Zhi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe-Xiong","family":"Lian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.clon.2010.05.004","article-title":"Thyroid cancer epidemiology and prognostic variables","volume":"22","author":"Sipos","year":"2010","journal-title":"Clin Oncol (R Coll Radiol)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2018.0128","article-title":"Time-varying pattern of mortality and recurrence from papillary thyroid cancer: Lessons from a long-term follow-up","volume":"29","author":"Dong","year":"2019","journal-title":"Thyroid"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2013.06.043","article-title":"Effect of reoperation on outcomes in papillary thyroid cancer","volume":"154","author":"Young","year":"2013","journal-title":"Surgery"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-0398-9","article-title":"Immunotherapy for advanced thyroid cancers - rationale, current advances and future strategies","volume":"16","author":"French","year":"2020","journal-title":"Nat Rev Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.80.12.8530576","article-title":"The correlation between papillary thyroid carcinoma and lymphocytic infiltration in the thyroid gland","volume":"80","author":"Matsubayashi","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-030342","article-title":"Papillary thyroid carcinomas from young adults and children contain a mixture of lymphocytes","volume":"88","author":"Modi","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.7150\/jca.44506","article-title":"Immune microenvironment of thyroid cancer","volume":"11","author":"Yin","year":"2020","journal-title":"J Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-012-9853-2","article-title":"Regulatory T cells and plasmacytoid dendritic cells contribute to the immune escape of papillary thyroid cancer coexisting with multinodular non-toxic goiter","volume":"44","author":"Yu","year":"2013","journal-title":"Endocrine"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2012.0560","article-title":"CD3(-)CD16(-)CD56(bright) immunoregulatory NK cells are increased in the tumor microenvironment and inversely correlate with advanced stages in patients with papillary thyroid cancer","volume":"23","author":"Gogali","year":"2013","journal-title":"Thyroid"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1838","article-title":"Phenotypical analysis of lymphocytes with suppressive and regulatory properties (Tregs) and NK cells in the papillary carcinoma of thyroid","volume":"97","author":"Gogali","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2019.01.021","article-title":"IL-10-producing b cells in differentiated thyroid cancer suppress the effector function of T cells but improve their survival upon activation","volume":"376","author":"Wang","year":"2019","journal-title":"Exp Cell Res"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20163934","article-title":"The immune landscape of thyroid cancer in the context of immune checkpoint inhibition","volume":"20","author":"Varricchi","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2012.04482.x","article-title":"Infiltration of a mixture of immune cells may be related to good prognosis in patients with differentiated thyroid carcinoma","volume":"77","author":"Cunha","year":"2012","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2564","article-title":"Tumor-associated lymphocytes and increased FoxP3+ regulatory T cell frequency correlate with more aggressive papillary thyroid cancer","volume":"95","author":"French","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"B16","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1038\/s41419-020-03294-z","article-title":"A new risk factor indicator for papillary thyroid cancer based on immune infiltration","volume":"12","author":"Yang","year":"2021","journal-title":"Cell Death Dis"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12586","article-title":"CD8+ tumour-infiltrating lymphocytes and COX2 expression may predict relapse in differentiated thyroid cancer","volume":"83","author":"Cunha","year":"2015","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1530\/erc-13-0436","article-title":"Lymphocytic profiling in thyroid cancer provides clues for failure of tumor immunity","volume":"21","author":"Imam","year":"2014","journal-title":"Endocr Relat Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s12094-014-1222-6","article-title":"Analysis of regulatory T cells frequency in peripheral blood and tumor tissues in papillary thyroid carcinoma with and without hashimoto's thyroiditis","volume":"17","author":"Liu","year":"2015","journal-title":"Clin Transl Oncol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1089\/thy.2017.0129","article-title":"European Perspective on 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: Proceedings of an interactive international symposium","volume":"29","author":"Luster","year":"2019","journal-title":"Thyroid"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.736068","article-title":"Integrative analysis of DNA methylation and gene expression identified follicular thyroid cancer-specific diagnostic biomarkers","volume":"12","author":"Yao","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509603102","article-title":"The role of microRNA genes in papillary thyroid carcinoma","volume":"102","author":"He","year":"2005","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B23","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1038\/bjc.2012.302","article-title":"A gene expression signature distinguishes normal tissues of sporadic and radiation-induced papillary thyroid carcinomas","volume":"107","author":"Dom","year":"2012","journal-title":"Br J Cancer"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610733104","article-title":"Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion","volume":"104","author":"Vasko","year":"2007","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"B26","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.immuni.2009.03.019","article-title":"Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor","volume":"30","author":"Miyara","year":"2009","journal-title":"Immunity"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00883","article-title":"Emerging functions of regulatory T cells in tissue homeostasis","volume":"9","author":"Sharma","year":"2018","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e1005","DOI":"10.1002\/cti2.1005","article-title":"Human FOXP3(+) T regulatory cell heterogeneity","volume":"7","author":"Mohr","year":"2018","journal-title":"Clin Transl Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1038\/s41590-018-0051-0","article-title":"Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR","volume":"19","author":"Zemmour","year":"2018","journal-title":"Nat Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.12.019","article-title":"Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade","volume":"18","author":"Charoentong","year":"2017","journal-title":"Cell Rep"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-16-3167","article-title":"PD-1 status in CD8(+) T cells associates with survival and anti-PD-1 therapeutic outcomes in head and neck cancer","volume":"77","author":"Kansy","year":"2017","journal-title":"Cancer Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1177\/0022034519882618","article-title":"CD103(+) T and dendritic cells indicate a favorable prognosis in oral cancer","volume":"98","author":"Xiao","year":"2019","journal-title":"J Dent Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-020-02563-2","article-title":"Tumor-infiltrating CD39(+)CD8(+) T cells determine poor prognosis and immune evasion in clear cell renal cell carcinoma patients","volume":"69","author":"Qi","year":"2020","journal-title":"Cancer Immunol Immunother"},{"key":"B34","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1515\/jpem.2003.16.1.63","article-title":"Analysis of changes in the percentage of b (CD19) and T (CD3) lymphocytes, subsets CD4, CD8 and their memory (CD45RO), and naive (CD45RA) T cells in children with immune and non-immune thyroid diseases","volume":"16","author":"Bossowski","year":"2003","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nri3442","article-title":"The integration of T cell migration, differentiation and function","volume":"13","author":"Masopust","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0034-2","article-title":"Tissue-specific functions of invariant natural killer T cells","volume":"18","author":"Crosby","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.570604","article-title":"Immune cell confrontation in the papillary thyroid carcinoma microenvironment","volume":"11","author":"Xie","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2020.101435","article-title":"Memory CD8(+) T cell responses to cancer","volume":"49","author":"Han","year":"2020","journal-title":"Semin Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1316796110","article-title":"Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans","volume":"110","author":"Sugiyama","year":"2013","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.182.3.1746","article-title":"Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer","volume":"182","author":"Tan","year":"2009","journal-title":"J Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.021","article-title":"Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells","volume":"45","author":"De Simone","year":"2016","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","first-page":":e002591","DOI":"10.1136\/jitc-2021-002591","article-title":"Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies","volume":"9","author":"Nishikawa","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nature10169","article-title":"Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and t(reg) cells","volume":"475","author":"Facciabene","year":"2011","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1172\/jci73639","article-title":"PD-1 identifies the patient-specific CD8\u207a tumor-reactive repertoire infiltrating human tumors","volume":"124","author":"Gros","year":"2014","journal-title":"J Clin Invest"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4051","article-title":"Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients","volume":"22","author":"Gros","year":"2016","journal-title":"Nat Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0235-4","article-title":"CD8(+) T cell states in human cancer: insights from single-cell analysis","volume":"20","author":"van der Leun","year":"2020","journal-title":"Nat Rev Cancer"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-4227","article-title":"Tumor-infiltrating T cells and the PD-1 checkpoint pathway in advanced differentiated and anaplastic thyroid cancer","volume":"101","author":"Bastman","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.Cir-14-0201","article-title":"PD-1+Tim-3+ CD8+ T lymphocytes display varied degrees of functional exhaustion in patients with regionally metastatic differentiated thyroid cancer","volume":"3","author":"Severson","year":"2015","journal-title":"Cancer Immunol Res"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0376-4","article-title":"Targeting CD39 in cancer","volume":"20","author":"Moesta","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.08.002","article-title":"Tissue-specific differentiation of CD8(+) resident memory T cells","volume":"42","author":"Yang","year":"2021","journal-title":"Trends Immunol"},{"key":"B51","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.tranon.2019.09.003","article-title":"Ectonucleotidase CD39 and checkpoint signalling receptor programmed death 1 are highly elevated in intratumoral immune cells in non-small-cell lung cancer","volume":"13","author":"T\u00f8ndell","year":"2020","journal-title":"Transl Oncol"},{"key":"B52","doi-asserted-by":"publisher","first-page":":e003078","DOI":"10.1136\/jitc-2021-003078","article-title":"B cells imprint adoptively transferred CD8(+) T cells with enhanced tumor immunity","volume":"10","author":"Smith","year":"2022","journal-title":"J Immunother Cancer"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301135","article-title":"Increased numbers of monocyte-derived dendritic cells during successful tumor immunotherapy with immune-activating agents","volume":"191","author":"Kuhn","year":"2013","journal-title":"J Immunol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-01167","article-title":"Immune profiling of thyroid carcinomas suggests the existence of two major phenotypes: An ATC-like and a PDTC-like","volume":"104","author":"Giannini","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-2287","article-title":"Long-term recurrence of small papillary thyroid cancer and its risk factors in a Korean multicenter study","volume":"102","author":"Hwangbo","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2018.0775","article-title":"Risk for thyroid cancer recurrence is higher in men than in women independent of disease stage at presentation","volume":"30","author":"Zahedi","year":"2020","journal-title":"Thyroid"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1530\/eje-12-0848","article-title":"Recurrence of differentiated thyroid cancer in the elderly","volume":"168","author":"Hollenbeak","year":"2013","journal-title":"Eur J Endocrinol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.894919\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T06:43:21Z","timestamp":1667803401000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.894919\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,7]]},"references-count":57,"alternative-id":["10.3389\/fimmu.2022.894919"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.894919","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,7]]},"article-number":"894919"}}