{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:55:33Z","timestamp":1781502933100,"version":"3.54.1"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Context<\/jats:title>\n Pituitary carcinoma is a rare and highly aggressive tumor. While anti-programmed cell death-1 (PD-1) therapy has shown efficacy in some cases, the factors that predict a favorable response remain largely unclear.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate tumor-infiltrating lymphocytes (TILs) in pituitary carcinoma and to compare T\u2212cell receptor (TCR) clonotypes between the pituitary and peripheral blood.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A 34-year-old woman with Lynch syndrome and adrenocorticotropic hormone-secreting pituitary carcinoma with hepatic metastasis received anti-PD-1 therapy, achieving durable disease control exceeding 1 year. Immunohistochemistry was performed on treatment-na\u00efve surgical tumor samples, and TCR repertoire analyses were conducted on both the tumor sample and peripheral blood mononuclear cells collected during effective anti-PD\u22121 therapy.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Treatment-na\u00efve pituitary carcinoma tissues exhibited infiltration of CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n T cells. Analysis of the TCR repertoire identified 15 clonotypes with a high frequency (&gt; 1% of sequencing reads) in the tumor; among these, four of the five most prevalent clonotypes were co-detected as dominant clones in peripheral blood after treatment, including the most abundant clones found within the CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n T cell populations. Despite control of the primary and hepatic lesions, ovarian metastasis developed, which was associated with reduced CD4\n +<\/jats:sup>\n TILs.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n The presence of CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n TILs may underlie the immunological foundation for PD-1 blockade efficacy in pituitary carcinoma, supported by the detection of tumor-resident TCR clonotypes in peripheral blood during a positive therapeutic response.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1876390","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:37:52Z","timestamp":1781501872000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dominant T cell receptor clonotypes in adrenocorticotropic hormone-secreting pituitary carcinoma are the highest-frequency clones among CD4+ and CD8+ cells in peripheral blood during effective anti-PD-1 therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Mariko","family":"Sugiyama","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Iwama","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhito","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Murase","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Hagiwara","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Immunology, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Nagata","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuta","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Akatsuka","sequence":"additional","affiliation":[{"name":"Department of Immunology, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Arima","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Diabetes, Nagoya University Graduate School of Medicine","place":["Nagoya, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad098","article-title":"Aggressive pituitary tumors and pituitary carcinomas: From pathology to treatment","volume":"108","author":"Burman","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-01401","article-title":"Corticotroph pituitary carcinoma in a patient with Lynch syndrome (LS) and pituitary tumors in a nationwide LS cohort","volume":"102","author":"Bengtsson","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1530\/erc-22-0037","article-title":"Immunotherapy in aggressive pituitary tumors and carcinomas: A systematic review","volume":"29","author":"Ilie","year":"2022","journal-title":"Endocr Relat Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e001532","DOI":"10.1136\/jitc-2020-001532","article-title":"Efficacy of pembrolizumab in patients with pituitary carcinoma: Report of four cases from a phase II study","volume":"8","author":"Majd","year":"2020","journal-title":"J Immunother Cancer"},{"key":"B5","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.cell.2018.12.034","article-title":"Defining T cell states associated with response to checkpoint immunotherapy in melanoma","volume":"175","author":"Sade-Feldman","year":"2018","journal-title":"Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab133","article-title":"Synergism of checkpoint inhibitors and peptide receptor radionuclide therapy in the treatment of pituitary carcinoma","volume":"5","author":"Lin","year":"2021","journal-title":"J Endocr Soc"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-01347","article-title":"Marked response of a hypermutated ACTH-secreting pituitary carcinoma to ipilimumab and nivolumab","volume":"103","author":"Lin","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B8","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3390\/jpm10030088","article-title":"Immunotherapy in corticotroph and lactotroph aggressive tumors and carcinomas: Two case reports and a review of the literature","volume":"10","author":"Duhamel","year":"2020","journal-title":"J Pers Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.576027","article-title":"Case report: A case of pituitary carcinoma treated with sequential dual immunotherapy and vascular endothelial growth factor inhibition therapy","volume":"11","author":"Lamb","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1530\/eje-20-0151","article-title":"Immune checkpoint inhibitor therapy for ACTH-secreting pituitary carcinoma: A new emerging treatment","volume":"184","author":"Sol","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1530\/eje-22-0440","article-title":"Aggressive pituitary tumours and carcinomas, characteristics and management of 171 patients","volume":"187","author":"Burman","year":"2022","journal-title":"Eur J Endocrinol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"4093","DOI":"10.3390\/cancers14174093","article-title":"Immunotherapy for aggressive and metastatic pituitary neuroendocrine tumors (PitNETs): State-of-the art","volume":"14","author":"Feola","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14645","article-title":"Should pituitary carcinoma be treated using a NET-like approach? A case of complete remission of a metastatic Malignant prolactinoma with multimodal therapy including immunotherapy","volume":"98","author":"Goichot","year":"2023","journal-title":"Clin Endocrinol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"5939","DOI":"10.1038\/s41598-023-33049-7","article-title":"Anti-tumor effects of anti-programmed cell death-1 antibody treatment are attenuated in streptozotocin-induced diabetic mice","volume":"13","author":"Ito","year":"2023","journal-title":"Sci Rep"},{"key":"B15","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s12865-016-0177-5","article-title":"A new high-throughput sequencing method for determining diversity and similarity of T cell receptor (TCR) alpha and beta repertoires and identifying potential new invariant TCR alpha chains","volume":"17","author":"Kitaura","year":"2016","journal-title":"BMC Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2021-002493","article-title":"Anti-pituitary antibodies and susceptible human leukocyte antigen alleles as predictive biomarkers for pituitary dysfunction induced by immune checkpoint inhibitors","volume":"9","author":"Kobayashi","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B17","doi-asserted-by":"publisher","first-page":"599-607","DOI":"10.1158\/2326-6066.cir-25-0693","article-title":"Concurrent pituitary and thyroid immune-related adverse events after immune checkpoint inhibitors associated with HLA-DR15-related haplotypes","volume":"14","author":"Kobayashi","year":"2026","journal-title":"Cancer Immunol Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.028","article-title":"Tumor and microenvironment evolution during immunotherapy with nivolumab","volume":"171","author":"Riaz","year":"2017","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.21417\/ky2019nm","article-title":"Clonal replacement of tumor-specific T cells following PD-1 blockade","volume":"25","author":"Yost","year":"2019","journal-title":"Nat Med"},{"key":"B20","doi-asserted-by":"publisher","first-page":"4098","DOI":"10.1038\/s41467-021-24343-x","article-title":"The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival","volume":"12","author":"Valpione","year":"2021","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"32147","DOI":"10.1038\/s41598-024-84009-8","article-title":"Dissociated response and treatment outcome with immune checkpoint blockade in advanced cancer","volume":"14","author":"Guan","year":"2024","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.01.008","article-title":"Hallmarks of response, resistance, and toxicity to immune checkpoint blockade","volume":"184","author":"Morad","year":"2021","journal-title":"Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.737615","article-title":"Editorial: CD4(+) T cells in cancer immunotherapies","volume":"12","author":"Gonzalez-Navajas","year":"2021","journal-title":"Front Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxw020","article-title":"Immune checkpoint inhibition in ovarian cancer","volume":"28","author":"Hamanishi","year":"2016","journal-title":"Int Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41574-024-01077-6","article-title":"Management, biomarkers and prognosis in people developing endocrinopathies associated with immune checkpoint inhibitors","volume":"21","author":"Iwama","year":"2025","journal-title":"Nat Rev Endocrinol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3803\/enm.2024.2180","article-title":"Combined PD-1 and CTLA-4 blockade increases the risks of multiple pituitary hormone deficiency and isolated adrenocorticotropic deficiency: A prospective study","volume":"40","author":"Iwama","year":"2025","journal-title":"Endocrinol Metab (Seoul)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1876390\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:37:55Z","timestamp":1781501875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1876390\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":26,"alternative-id":["10.3389\/fimmu.2026.1876390"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1876390","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]},"article-number":"1876390"}}