{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:15:50Z","timestamp":1791296150152,"version":"4.1.0"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>CD8+ T cells play a central role in cancer immunosurveillance, and the efficient induction of CTLs against tumor Ags is required for successful immunotherapy for cancer patients. Notch signaling directly regulates the transcription of effector molecules in CTLs. However, it remains unclear whether Notch signaling in CD8+ T cells is required for antitumor CTL responses and whether modulation of Notch signaling can augment antitumor CTL responses. In this study, we demonstrate that signaling by Notch2 but not Notch1 in CD8+ T cells is required for antitumor CTL responses. Notch2flox\/flox mice crossed with E8I-cre transgenic (N2F\/F-E8I) mice, in which the Notch2 gene is absent only in CD8+ T cells, die earlier than control mice after inoculation with OVA-expressing EG7 thymoma cells. In contrast, Notch1flox\/flox mice crossed with E8I-cre transgenic mice inoculated with EG7 cells die comparable to control mice, indicating that Notch2 is crucial for exerting antitumor CTL responses. Injection of anti-Notch2 agonistic Ab or delta-like 1-overexpressing dendritic cells augmented the antitumor response in C57BL\/6 mice inoculated with EG7 cells. These findings indicate that Notch2 signaling in CD8+ T cells is required for generating potent antitumor CTLs, thus providing a crucial target for augmenting tumor immune responses.<\/jats:p>","DOI":"10.4049\/jimmunol.0903661","type":"journal-article","created":{"date-parts":[[2010,3,30]],"date-time":"2010-03-30T03:34:10Z","timestamp":1269920050000},"page":"4673-4678","source":"Crossref","is-referenced-by-count":84,"title":["Notch2 Signaling Is Required for Potent Antitumor Immunity In Vivo"],"prefix":"10.1093","volume":"184","author":[{"given":"Koji","family":"Sugimoto","sequence":"first","affiliation":[{"name":"*Department of Immunology and Parasitology and"},{"name":"\u2020Department of Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Maekawa","sequence":"additional","affiliation":[{"name":"*Department of Immunology and Parasitology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Kitamura","sequence":"additional","affiliation":[{"name":"*Department of Immunology and Parasitology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Nishida","sequence":"additional","affiliation":[{"name":"*Department of Immunology and Parasitology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akemi","family":"Koyanagi","sequence":"additional","affiliation":[{"name":"\u2021Division of Cell Biology, Biomedical Research Center and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Yagita","sequence":"additional","affiliation":[{"name":"\u00a7Department of Immunology, Juntendo University School of Medicine, Tokyo;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidefumi","family":"Kojima","sequence":"additional","affiliation":[{"name":"\u00b6Department of Immunology, Dokkyo Medical University, Tochigi; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Chiba","sequence":"additional","affiliation":[{"name":"\u2016Department of Clinical and Experimental Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Shimada","sequence":"additional","affiliation":[{"name":"\u2020Department of Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Yasutomo","sequence":"additional","affiliation":[{"name":"*Department of Immunology and Parasitology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,5,1]]},"reference":[{"key":"2023010203031727700_r1","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nri2326","article-title":"Inhibitory B7-family molecules in the tumour microenvironment.","volume":"8","author":"Zou","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2023010203031727700_r2","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1038\/nri2438","article-title":"Immunotherapy of autoimmunity and cancer: the penalty for success.","volume":"8","author":"Caspi","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"2023010203031727700_r3","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1084\/jem.194.6.823","article-title":"Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses.","volume":"194","author":"Sutmuller","year":"2001","journal-title":"J. Exp. Med."},{"key":"2023010203031727700_r4","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1038\/nm863","article-title":"Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity.","volume":"9","author":"Curiel","year":"2003","journal-title":"Nat. Med."},{"key":"2023010203031727700_r5","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/ni1045","article-title":"Notch regulation of lymphocyte development and function.","volume":"5","author":"Radtke","year":"2004","journal-title":"Nat. Immunol."},{"key":"2023010203031727700_r6","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1146\/annurev.immunol.23.021704.115747","article-title":"Regulation of lymphoid development, differentiation, and function by the Notch pathway.","volume":"23","author":"Maillard","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"2023010203031727700_r7","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1038\/nri1998","article-title":"Notch signalling during peripheral T-cell activation and differentiation.","volume":"7","author":"Osborne","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"2023010203031727700_r8","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/ni.1649","article-title":"Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity.","volume":"9","author":"Maekawa","year":"2008","journal-title":"Nat. Immunol."},{"key":"2023010203031727700_r9","doi-asserted-by":"crossref","first-page":"7010","DOI":"10.1073\/pnas.0709919105","article-title":"Dendritic cell-mediated NK cell activation is controlled by Jagged2\u2013Notch interaction.","volume":"105","author":"Kijima","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023010203031727700_r10","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/S1074-7613(03)00111-0","article-title":"Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development.","volume":"18","author":"Saito","year":"2003","journal-title":"Immunity"},{"key":"2023010203031727700_r11","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S1074-7613(03)00270-X","article-title":"Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells.","volume":"19","author":"Maekawa","year":"2003","journal-title":"Immunity"},{"key":"2023010203031727700_r12","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/sj.gt.3301206","article-title":"Plat-E: an efficient and stable system for transient packaging of retroviruses.","volume":"7","author":"Morita","year":"2000","journal-title":"Gene Ther."},{"key":"2023010203031727700_r13","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1128\/MCB.00863-07","article-title":"Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1.","volume":"28","author":"Tagami","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2023010203031727700_r14","doi-asserted-by":"crossref","first-page":"7109","DOI":"10.4049\/jimmunol.173.12.7109","article-title":"Notch governing mature T cell differentiation.","volume":"173","author":"Tsukumo","year":"2004","journal-title":"J. Immunol."},{"key":"2023010203031727700_r15","doi-asserted-by":"crossref","first-page":"3380","DOI":"10.4049\/jimmunol.0802598","article-title":"Notch regulates cytolytic effector function in CD8+ T cells.","volume":"182","author":"Cho","year":"2009","journal-title":"J. Immunol."},{"key":"2023010203031727700_r16","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1111\/j.1600-065X.2009.00791.x","article-title":"Regulation of Notch signaling during T- and B-cell development by O-fucose glycans.","volume":"230","author":"Stanley","year":"2009","journal-title":"Immunol. Rev."},{"key":"2023010203031727700_r17","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nature05313","article-title":"Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis.","volume":"444","author":"Ridgway","year":"2006","journal-title":"Nature"},{"key":"2023010203031727700_r18","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1038\/nature05355","article-title":"Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.","volume":"444","author":"Noguera-Troise","year":"2006","journal-title":"Nature"},{"key":"2023010203031727700_r19","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/nature05577","article-title":"Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries.","volume":"445","author":"Siekmann","year":"2007","journal-title":"Nature"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.aai.org\/jimmunol\/article-pdf\/184\/9\/4673\/1323916\/ji_0903661.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.aai.org\/jimmunol\/article-pdf\/184\/9\/4673\/1323916\/ji_0903661.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,2]],"date-time":"2025-01-02T17:59:09Z","timestamp":1735840749000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.aai.org\/jimmunol\/article\/184\/9\/4673\/83245\/Notch2-Signaling-Is-Required-for-Potent-Antitumor"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,5,1]]},"references-count":19,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2010,5,1]]},"published-print":{"date-parts":[[2010,5,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0903661","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,5,1]]}}}