{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360021389814964352.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1097/cji.0000000000000503"}},{"identifier":{"@type":"URI","@value":"https://journals.lww.com/10.1097/CJI.0000000000000503"}}],"resourceType":"学術雑誌論文(journal article)","dc:title":[{"@value":"Inhibition of PTPN3 Expressed in Activated Lymphocytes Enhances the Antitumor Effects of Anti-PD-1 Therapy in Head and Neck Cancer, Especially in Hypoxic Environments"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:p>In the tumor microenvironment, wherein cytotoxic lymphocytes interact with cancer cells, lymphocyte exhaustion, an immune checkpoint inhibitor target, is promoted. However, the efficacy of these inhibitors is limited, and improving response rates remains challenging. We previously reported that protein tyrosine phosphatase nonreceptor type (PTPN) 3 is a potential immune checkpoint molecule for activated lymphocytes and that PTPN3 inhibition should be a focus area for cancer immunotherapy development. Therefore, in this study, we focused on PTPN3-suppressive therapy in terms of lymphocyte exhaustion under hypoxic conditions, which are a cancer microenvironment, and investigated measures for improving the response to anti-programmed death receptor (PD)-1 antibody drugs. We found that PTPN3 expression was upregulated in activated lymphocytes under hypoxic conditions, similar to the findings for other immune checkpoint molecules, such as PD-1, T cell immunoglobulin mucin-3, and lymphocyte-activation gene-3; furthermore, it functioned as a lymphocyte exhaustion marker. In addition, PTPN3-suppressed activated lymphocytes promoted the mammalian target of rapamycin (mTOR)-Akt signaling pathway activation and enhanced proliferation, migration, and cytotoxic activities under hypoxic conditions. Furthermore, PTPN3 suppression in activated lymphocytes increased PD-1 expression and enhanced the antitumor effects of anti-PD-1 antibody drugs against head and neck cancer in vitro and in vivo. These results suggest that the suppression of PTPN3 expression in activated lymphocytes enhances the therapeutic effect of anti-PD-1 antibody drugs in head and neck cancer, especially under hypoxic conditions that cause lymphocyte exhaustion.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380021389814964368","@type":"Researcher","foaf:name":[{"@value":"Shogo Masuda"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"},{"@value":"Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1420564276184209024","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"30553276"},{"@type":"NRID","@value":"1000030553276"},{"@type":"NRID","@value":"9000018718977"},{"@type":"NRID","@value":"9000253365069"},{"@type":"NRID","@value":"9000237601202"},{"@type":"NRID","@value":"9000001767447"},{"@type":"NRID","@value":"9000022070614"},{"@type":"NRID","@value":"9000256625840"},{"@type":"NRID","@value":"9000256626626"},{"@type":"NRID","@value":"9000019061272"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/Hide-o"}],"foaf:name":[{"@value":"Hideya Onishi"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964353","@type":"Researcher","foaf:name":[{"@value":"Naoya Iwamoto"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964369","@type":"Researcher","foaf:name":[{"@value":"Akira Imaizumi"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964484","@type":"Researcher","foaf:name":[{"@value":"Satoko Koga"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964364","@type":"Researcher","foaf:name":[{"@value":"Shinjiro Nagao"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964356","@type":"Researcher","foaf:name":[{"@value":"Keita Sakanashi"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964374","@type":"Researcher","foaf:name":[{"@value":"Shinsaku Itoyama"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"},{"@value":"Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964485","@type":"Researcher","foaf:name":[{"@value":"Akiko Fujimura"}],"jpcoar:affiliationName":[{"@value":"Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"},{"@value":"Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964487","@type":"Researcher","foaf:name":[{"@value":"Noritaka Komune"}],"jpcoar:affiliationName":[{"@value":"Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1420564276190752640","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"90529885"},{"@type":"NRID","@value":"1000090529885"},{"@type":"NRID","@value":"9000345382019"},{"@type":"NRID","@value":"9000017289581"},{"@type":"NRID","@value":"9000388536676"},{"@type":"NRID","@value":"9000388536696"},{"@type":"NRID","@value":"9000311508497"},{"@type":"NRID","@value":"9000369747794"},{"@type":"NRID","@value":"9000321625869"},{"@type":"NRID","@value":"9000256834238"},{"@type":"NRID","@value":"9000258257873"},{"@type":"NRID","@value":"9000256834505"},{"@type":"NRID","@value":"9000311508492"},{"@type":"NRID","@value":"9000258257843"},{"@type":"NRID","@value":"9000402248667"},{"@type":"NRID","@value":"9000405101456"},{"@type":"NRID","@value":"9000406043136"},{"@type":"NRID","@value":"9000402264099"},{"@type":"RESEARCHMAP","@value":"https://researchmap.jp/ryukogo"}],"foaf:name":[{"@value":"Ryunosuke Kogo"}],"jpcoar:affiliationName":[{"@value":"Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964367","@type":"Researcher","foaf:name":[{"@value":"Masayo Umebayashi"}],"jpcoar:affiliationName":[{"@value":"Fukuoka General Cancer Clinic, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964373","@type":"Researcher","foaf:name":[{"@value":"Takashi Morisaki"}],"jpcoar:affiliationName":[{"@value":"Fukuoka General Cancer Clinic, Fukuoka, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380021389814964377","@type":"Researcher","foaf:name":[{"@value":"Takashi Nakagawa"}],"jpcoar:affiliationName":[{"@value":"Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"15249557"}],"prism:publicationName":[{"@value":"Journal of Immunotherapy"}],"dc:publisher":[{"@value":"Ovid Technologies (Wolters Kluwer Health)"}],"prism:publicationDate":"2024-02-01","prism:volume":"47","prism:number":"3","prism:startingPage":"89","prism:endingPage":"97"},"reviewed":"false","url":[{"@id":"https://journals.lww.com/10.1097/CJI.0000000000000503"}],"createdAt":"2024-02-01","modifiedAt":"2025-08-03","project":[{"@id":"https://cir.nii.ac.jp/crid/1040010457616477440","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"22K08715"},{"@type":"JGN","@value":"JP22K08715"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22K08715/"}],"notation":[{"@language":"ja","@value":"PTPN3を標的とする非抗体型免疫チェックポイント阻害剤を用いた癌免疫治療開発"},{"@language":"en","@value":"Development of cancer immunotherapy using non-receptor type immune checkpoint inhibitor targeting PTPN3"}]},{"@id":"https://cir.nii.ac.jp/crid/1040014327097173120","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"23K08132"},{"@type":"JGN","@value":"JP23K08132"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23K08132/"}],"notation":[{"@language":"ja","@value":"再酸素化によるC4orf47発現変化に焦点をおいた新たな膵癌転移メカニズムの解析"},{"@language":"en","@value":"Analysis of the mechanism of pancreatic cancer metastasis targeting the kinetics of C4orf47 expression by reoxygenation"}]},{"@id":"https://cir.nii.ac.jp/crid/1040014327097246464","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"23K08298"},{"@type":"JGN","@value":"JP23K08298"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23K08298/"}],"notation":[{"@language":"ja","@value":"MAML3-Hh/NOTCH新規経路を標的とした新たな肺癌治療法の開発"},{"@language":"en","@value":"Development of a new lung cancer therapy targeting a MAML3-Hh/NOTCH signaling pathway"}]},{"@id":"https://cir.nii.ac.jp/crid/1040018351902963584","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"23K24422"},{"@type":"JGN","@value":"JP23K24422"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23K24422/"}],"notation":[{"@language":"ja","@value":"肺NETが有するPTPN3-CACNA1G-TKリン酸化経路の解析と治療への応用"},{"@language":"en","@value":"Analysis of PTPN3-CACNA1G-TK phosphorylation pathway in lung NET"}]},{"@id":"https://cir.nii.ac.jp/crid/1040287907244755968","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"21K09561"},{"@type":"JGN","@value":"JP21K09561"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21K09561/"}],"notation":[{"@language":"ja","@value":"臨床応用を目指した頭頸部癌におけるctDNAモニタリングシステムの構築"},{"@language":"en","@value":"Establishment of ctDNA monitoring system in HNSCC"}]},{"@id":"https://cir.nii.ac.jp/crid/1040569382215333632","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"21K08712"},{"@type":"JGN","@value":"JP21K08712"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21K08712/"}],"notation":[{"@language":"ja","@value":"MAML3を標的としたHh/Notch両シグナル阻害による新規胆嚢癌治療開発"},{"@language":"en","@value":"Development of a new therapeutic strategy for gallbladder cancer targeting MAML3 by the inhibition of both Hh and Notch signaling"}]},{"@id":"https://cir.nii.ac.jp/crid/1040577277050569216","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"23K08073"},{"@type":"JGN","@value":"JP23K08073"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23K08073/"}],"notation":[{"@language":"ja","@value":"ネオ抗原パルス成熟樹状細胞が分泌するエクソソームを用いた新たな癌免疫治療法の開発"},{"@language":"en","@value":"Development of a new cancer immunotherapy using the exosome derived from neoantigen pulsed mature dendritic cells"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360005515810012416","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"PTPN3 expressed in activated T lymphocytes is a candidate for a non-antibody-type immune checkpoint inhibitor"}]},{"@id":"https://cir.nii.ac.jp/crid/1360011145751630080","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Combinatorial control of the specificity of protein tyrosine phosphatases"}]},{"@id":"https://cir.nii.ac.jp/crid/1360021395150098304","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Immune checkpoint therapy—current perspectives and future directions"}]},{"@id":"https://cir.nii.ac.jp/crid/1360283692365664640","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2"}]},{"@id":"https://cir.nii.ac.jp/crid/1360290617824691200","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"FAM115C could be a novel tumor suppressor associated with prolonged survival in pancreatic cancer patients"}]},{"@id":"https://cir.nii.ac.jp/crid/1360302870445278080","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer: Results from a Prospective Imaging Trial"}]},{"@id":"https://cir.nii.ac.jp/crid/1360565165796617600","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"CD24 suppresses malignant phenotype by downregulation of SHH transcription through STAT1 inhibition in breast cancer cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1360567181983536640","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Hypoxia but not normoxia promotes Smoothened transcription through upregulation of RBPJ and Mastermind-like 3 in pancreatic cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574094138849792","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1360574094997240192","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The blockade of immune checkpoints in cancer immunotherapy"}]},{"@id":"https://cir.nii.ac.jp/crid/1360576118762078720","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"PTPN3 is a potential target for a new cancer immunotherapy that has a dual effect of T cell activation and direct cancer inhibition in lung neuroendocrine tumor"}]},{"@id":"https://cir.nii.ac.jp/crid/1360579817454380032","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck"}]},{"@id":"https://cir.nii.ac.jp/crid/1360579820064640000","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion"}]},{"@id":"https://cir.nii.ac.jp/crid/1360584346088202880","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"The tumor microenvironment shapes the molecular characteristics of exhausted CD8+ T cells"}]},{"@id":"https://cir.nii.ac.jp/crid/1360853567389900032","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms"}]},{"@id":"https://cir.nii.ac.jp/crid/1360865818712510464","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity"}]},{"@id":"https://cir.nii.ac.jp/crid/1360865819389412480","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Construction of a hypoxia-derived gene model to predict the prognosis and therapeutic response of head and neck squamous cell carcinoma"}]},{"@id":"https://cir.nii.ac.jp/crid/1360865820080900736","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Targeting protein phosphatases in cancer immunotherapy and autoimmune disorders"}]},{"@id":"https://cir.nii.ac.jp/crid/1361131417449545856","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"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"}]},{"@id":"https://cir.nii.ac.jp/crid/1361137046374528000","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling"}]},{"@id":"https://cir.nii.ac.jp/crid/1361981471035930880","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544419178589824","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Importance of culturing primary lymphocytes at physiological oxygen levels"}]},{"@id":"https://cir.nii.ac.jp/crid/1362544420132725504","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints"}]},{"@id":"https://cir.nii.ac.jp/crid/1362825894024710528","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388845639902464","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen"}]},{"@id":"https://cir.nii.ac.jp/crid/1363388845844562944","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670320881868544","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment"}]},{"@id":"https://cir.nii.ac.jp/crid/1363670321252048512","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Culturing at atmospheric oxygen levels impacts lymphocyte function"}]},{"@id":"https://cir.nii.ac.jp/crid/1364233268319290752","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"<i>In Vitro</i>\n                    Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and\n                    <i>In Vivo</i>\n                    Toxicology in Non-Human Primates"}]},{"@id":"https://cir.nii.ac.jp/crid/1370021389814964366","@type":"Product","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Liprin-α4 as a possible new therapeutic target for pancreatic cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1370021389814964483","@type":"Product","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer"}]},{"@id":"https://cir.nii.ac.jp/crid/1370305492850993408","@type":"Product","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1097/cji.0000000000000503"},{"@type":"KAKEN","@value":"PRODUCT-25726602"},{"@type":"KAKEN","@value":"PRODUCT-25726729"},{"@type":"KAKEN","@value":"PRODUCT-25727051"},{"@type":"KAKEN","@value":"PRODUCT-25503556"},{"@type":"KAKEN","@value":"PRODUCT-25526371"},{"@type":"KAKEN","@value":"PRODUCT-25470654"},{"@type":"KAKEN","@value":"PRODUCT-25502728"},{"@type":"OPENAIRE","@value":"doi_________::b2474409ebf7da0915fd25c230e42710"}]}