{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T22:25:37Z","timestamp":1790634337408,"version":"4.1.0"},"reference-count":59,"publisher":"BMJ","issue":"5","license":[{"start":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T00:00:00Z","timestamp":1652659200000},"content-version":"unspecified","delay-in-days":15,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 31825011"],"award-info":[{"award-number":["No. 31825011"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 32030041"],"award-info":[{"award-number":["No. 32030041"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 81702443"],"award-info":[{"award-number":["No. 81702443"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,4,6]]},"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Antitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8<jats:sup>+<\/jats:sup> T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8<jats:sup>+<\/jats:sup> T-cell epitopes can drive the functional exhaustion of tumor-specific CD8<jats:sup>+<\/jats:sup> T cells. Tumor-specific type-I helper CD4<jats:sup>+<\/jats:sup> T (T<jats:sub>H<\/jats:sub>1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8<jats:sup>+<\/jats:sup> T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4<jats:sup>+<\/jats:sup> T-cell epitopes to induce tumor-specific T<jats:sub>H<\/jats:sub>1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific T<jats:sub>H<\/jats:sub>1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1\/PD-L1 immunotherapy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                     <jats:italic>Listeria monocytogenes<\/jats:italic> vector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-A<jats:sup>b<\/jats:sup>-restricted CD4<jats:sup>+<\/jats:sup> T cell epitope (GP<jats:sub>61\u201380<\/jats:sub>) or ovalbumin-specific CD4<jats:sup>+<\/jats:sup> T cell epitope (OVA<jats:sub>323-339<\/jats:sub>) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4<jats:sup>+<\/jats:sup> T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>CD4<jats:sup>+<\/jats:sup> T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific T<jats:sub>H<\/jats:sub>1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8<jats:sup>+<\/jats:sup> T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8<jats:sup>+<\/jats:sup> T cells.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>CD4<jats:sup>+<\/jats:sup> T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific T<jats:sub>H<\/jats:sub>1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1\/PD-L1 immune checkpoint blockade (ICB) against cancer.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2021-004022","type":"journal-article","created":{"date-parts":[[2022,5,23]],"date-time":"2022-05-23T13:39:53Z","timestamp":1653313193000},"page":"e004022","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["CD4<sup>+<\/sup> T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1\/PD-L1 immunotherapy"],"prefix":"10.1136","volume":"10","author":[{"given":"Minglu","family":"Xiao","sequence":"first","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"},{"name":"Department of Dermatology, the Fourth Medical Center, Chinese PLA General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luoyingzi","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoshuai","family":"Cao","sequence":"additional","affiliation":[{"name":"Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shun","family":"Lei","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"},{"name":"Department of Aviation Physiology Training, Qingdao Special Servicemen Recuperation Center of PLA Navy, Qingdao, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengcheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Nephrology, Jinling Hospital National Clinical Research Center of Kidney Diseases, Nanjing, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengping","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Immunology, Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Fang","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingxing","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Cancer, Third Military Medical University Second Affiliated Hospital, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhao","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifan","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyi","family":"Guo","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqiong","family":"Wen","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Stomatological Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfang","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisha","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, University of Chinese Academy of Sciences, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yao","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiang","family":"Ye","sequence":"additional","affiliation":[{"name":"Key Laboratory of Jiangsu Preventive Veterinary Medicine, Key Laboratory for Avian Preventive Medicine, Ministry of Education, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"He","sequence":"additional","affiliation":[{"name":"Department of Immunology, Huazhong University of Science and Technology Tongji Medical College School of Basic Medicine, Wuhan, Hubei, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0271-4384","authenticated-orcid":false,"given":"Jun","family":"Huang","sequence":"additional","affiliation":[{"name":"Pritzker School of Molecular Engineering, University of Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0778-3311","authenticated-orcid":false,"given":"Lilin","family":"Ye","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Third Military Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2022,5,17]]},"reference":[{"key":"2025100315175894000_10.5.e004022.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-041015-055318"},{"key":"2025100315175894000_10.5.e004022.2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035"},{"key":"2025100315175894000_10.5.e004022.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.023"},{"key":"2025100315175894000_10.5.e004022.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar4060"},{"key":"2025100315175894000_10.5.e004022.5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003466"},{"key":"2025100315175894000_10.5.e004022.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature14011"},{"key":"2025100315175894000_10.5.e004022.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1412082"},{"key":"2025100315175894000_10.5.e004022.8","doi-asserted-by":"publisher","DOI":"10.1038\/nature13904"},{"key":"2025100315175894000_10.5.e004022.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2018.06.001"},{"key":"2025100315175894000_10.5.e004022.10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1509660"},{"key":"2025100315175894000_10.5.e004022.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1510665"},{"key":"2025100315175894000_10.5.e004022.12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507643"},{"key":"2025100315175894000_10.5.e004022.13","doi-asserted-by":"crossref","first-page":"127r","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":"2025100315175894000_10.5.e004022.14","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005374"},{"key":"2025100315175894000_10.5.e004022.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.001"},{"key":"2025100315175894000_10.5.e004022.16","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.8.4911-4927.2003"},{"key":"2025100315175894000_10.5.e004022.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809818106"},{"key":"2025100315175894000_10.5.e004022.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0044-0"},{"key":"2025100315175894000_10.5.e004022.19","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.coi.2017.07.004","article-title":"Vaccines targeting helper T cells for cancer immunotherapy","volume":"47","author":"Melssen","year":"2017","journal-title":"Curr Opin Immunol"},{"key":"2025100315175894000_10.5.e004022.20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2008.00616.x"},{"key":"2025100315175894000_10.5.e004022.21","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.11.6047"},{"key":"2025100315175894000_10.5.e004022.22","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(90)90591-2"},{"key":"2025100315175894000_10.5.e004022.23","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2205"},{"key":"2025100315175894000_10.5.e004022.24","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.12.2057"},{"key":"2025100315175894000_10.5.e004022.25","doi-asserted-by":"publisher","DOI":"10.1038\/30996"},{"key":"2025100315175894000_10.5.e004022.26","doi-asserted-by":"publisher","DOI":"10.1038\/31002"},{"key":"2025100315175894000_10.5.e004022.27","doi-asserted-by":"publisher","DOI":"10.1038\/30989"},{"key":"2025100315175894000_10.5.e004022.28","doi-asserted-by":"publisher","DOI":"10.1038\/nature08511"},{"key":"2025100315175894000_10.5.e004022.29","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-1322"},{"key":"2025100315175894000_10.5.e004022.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.10.009"},{"key":"2025100315175894000_10.5.e004022.31","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/cmi.2017.3","article-title":"Efficient control of chronic LCMV infection by a CD4 T cell epitope-based heterologous prime-boost vaccination in a murine model","volume":"15","author":"He","year":"2018","journal-title":"Cell Mol Immunol"},{"key":"2025100315175894000_10.5.e004022.32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.9.5202"},{"key":"2025100315175894000_10.5.e004022.33","article-title":"Influenza: propagation, quantification, and storage","volume":"Chapter 15","author":"Szretter","year":"2006","journal-title":"Curr Protoc Microbiol"},{"key":"2025100315175894000_10.5.e004022.34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2017.04.017"},{"key":"2025100315175894000_10.5.e004022.35","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00806"},{"key":"2025100315175894000_10.5.e004022.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"2025100315175894000_10.5.e004022.37","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.immuni.2019.11.002","article-title":"Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection","volume":"51","author":"Hudson","year":"2019","journal-title":"Immunity"},{"key":"2025100315175894000_10.5.e004022.38","doi-asserted-by":"publisher","DOI":"10.1038\/nature19317"},{"key":"2025100315175894000_10.5.e004022.39","doi-asserted-by":"publisher","DOI":"10.1038\/nature19330"},{"key":"2025100315175894000_10.5.e004022.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.12.021"},{"key":"2025100315175894000_10.5.e004022.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.11.014"},{"key":"2025100315175894000_10.5.e004022.42","doi-asserted-by":"publisher","DOI":"10.1038\/nm0595-471"},{"key":"2025100315175894000_10.5.e004022.43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.9.3987"},{"key":"2025100315175894000_10.5.e004022.44","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1998.9330"},{"key":"2025100315175894000_10.5.e004022.45","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.4049\/jimmunol.153.10.4636","article-title":"Influenza and vaccinia viruses expressing malaria CD8+ T and B cell epitopes. Comparison of their immunogenicity and capacity to induce protective immunity","volume":"153","author":"Rodrigues","year":"1994","journal-title":"J Immunol"},{"key":"2025100315175894000_10.5.e004022.46","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2020.1737369"},{"key":"2025100315175894000_10.5.e004022.47","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.00935-20","article-title":"T cell receptor diversity and lineage relationship between virus-specific CD8 T cell subsets during chronic lymphocytic choriomeningitis virus infection","volume":"94","author":"Chang","year":"2020","journal-title":"J Virol"},{"key":"2025100315175894000_10.5.e004022.48","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf2807"},{"key":"2025100315175894000_10.5.e004022.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.08.065"},{"key":"2025100315175894000_10.5.e004022.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.004"},{"key":"2025100315175894000_10.5.e004022.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.07.020"},{"key":"2025100315175894000_10.5.e004022.52","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100348"},{"key":"2025100315175894000_10.5.e004022.53","doi-asserted-by":"publisher","DOI":"10.1038\/nri3254"},{"key":"2025100315175894000_10.5.e004022.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0088-1"},{"key":"2025100315175894000_10.5.e004022.55","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aav7431","article-title":"Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy","volume":"12","author":"Mayoux","year":"2020","journal-title":"Sci Transl Med"},{"key":"2025100315175894000_10.5.e004022.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.03.012"},{"key":"2025100315175894000_10.5.e004022.57","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1016\/j.immuni.2021.08.026","article-title":"Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes","volume":"54","author":"Schenkel","year":"2021","journal-title":"Immunity"},{"key":"2025100315175894000_10.5.e004022.58","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862"},{"key":"2025100315175894000_10.5.e004022.59","doi-asserted-by":"publisher","DOI":"10.1126\/science.aae0491"}],"updated-by":[{"DOI":"10.1136\/jitc-2021-004022corr1","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,10,25]],"date-time":"2022-10-25T00:00:00Z","timestamp":1666656000000}}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2021-004022","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T22:18:09Z","timestamp":1759529889000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2021-004022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5]]},"references-count":59,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5,17]]},"published-print":{"date-parts":[[2022,5]]}},"alternative-id":["10.1136\/jitc-2021-004022"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2021-004022","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5]]}}}