{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T15:21:42Z","timestamp":1768404102298,"version":"3.49.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:00:00Z","timestamp":1614297600000},"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:p>Oncolytic viruses are of growing importance in cancer therapeutics since they combine direct oncolytic effect and the stimulation of antitumor immunity. Emerging evidences showed that the function of oncolytic viruses is dependent on immune response in tumor microenvironment, and the modulation of immunity could influence their efficacy. Here we combined the interleukin 10 (IL-10) and oncolytic adenovirus Ad-hTERT to treat lung cancer and explored the underlying mechanism under combination therapy. Lewis lung carcinoma (LLC) and B16F10 tumor-bearing immunocompetent C57BL\/6 mice that received Ad-hTERT or IL-10 alone showed mild antitumor effect, while the combination therapy shrink tumor bulks and prolonged survival remarkably. In addition, IL-10 didn\u2019t show direct influence on tumor cell viability or Ad-hTERT mediated tumor cell lysis <jats:italic>in vitro<\/jats:italic>. To further explore the influence of combination therapy mediated antitumor capacity, we eliminated CD8<jats:sup>+<\/jats:sup> T, CD4<jats:sup>+<\/jats:sup> T or natural killer (NK) cells in LLC and B16F10-bearing C57BL\/6 mice, and found that CD8<jats:sup>+<\/jats:sup> T cells were critical mediator in the combination therapy. The combination therapy induced intensive infiltration of CD8<jats:sup>+<\/jats:sup> T cells in tumors, increased tumor-specific IFN-\u03b3 secretion by CD8<jats:sup>+<\/jats:sup> T cells. The long-term tumor-specific immune memory induced by the combination therapy rejected rechallenge by respective tumor cell lines. This study demonstrated that the therapy combining IL-10 and Ad-hTERT augmented antitumor efficacy which was CD8<jats:sup>+<\/jats:sup> T cells dependent. Our findings paved the way to combine cytokines and oncolytic viruses to enhance antitumor immunotherapy in treating cancer.<\/jats:p>","DOI":"10.3389\/fimmu.2021.615089","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T06:45:07Z","timestamp":1614321907000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Combining IL-10 and Oncolytic Adenovirus Demonstrates Enhanced Antitumor Efficacy Through CD8+ T Cells"],"prefix":"10.3389","volume":"12","author":[{"given":"Duo","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luyu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuhui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.2174\/1568009617666170206111609","article-title":"Oncolytic Viruses: The Best is Yet to Come","volume":"18","author":"Lemay","year":"2018","journal-title":"Curr Cancer Drug Targets"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5116","article-title":"Going viral: a review of replication-selective oncolytic adenoviruses","volume":"6","author":"Larson","year":"2015","journal-title":"Oncotarget"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10060201","article-title":"Designer Oncolytic Adenovirus: Coming of Age","volume":"10","author":"Baker","year":"2018","journal-title":"Cancers (Basel)"},{"key":"B4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.coviro.2016.06.009","article-title":"Recent advances in oncolytic adenovirus therapies for cancer","volume":"21","author":"Rosewell Shaw","year":"2016","journal-title":"Curr Opin Virol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-016-1453-9","article-title":"Oncolytic viruses-immunotherapeutics on the rise","volume":"94","author":"Keller","year":"2016","journal-title":"J Mol Med (Berl)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0477","article-title":"The Efficacy of Oncolytic Adenovirus Is Mediated by T-cell Responses against Virus and Tumor in Syrian Hamster Model","volume":"23","author":"Li","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2010.161","article-title":"Treatment of cancer patients with a serotype 5\/3 chimeric oncolytic adenovirus expressing GMCSF","volume":"18","author":"Koski","year":"2010","journal-title":"Mol Ther"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1038\/s41467-017-01385-8","article-title":"Re-designing Interleukin-12 to enhance its safety and potential as an anti-tumor immunotherapeutic agent","volume":"8","author":"Wang","year":"2017","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/0968-0004(91)90155-O","article-title":"Telomeres","volume":"16","author":"Blackburn","year":"1991","journal-title":"Trends Biochem Sci"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202752","article-title":"Repression of an alternative mechanism for lengthening of telomeres in somatic cell hybrids","volume":"18","author":"Perrem","year":"1999","journal-title":"Oncogene"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/337331a0","article-title":"A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis","volume":"337","author":"Greider","year":"1989","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.368282","article-title":"Human telomerase reverse transcriptase (hTERT) is a novel target of the Wnt\/beta-catenin pathway in human cancer","volume":"287","author":"Zhang","year":"2012","journal-title":"J Biol Chem"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2015.3047","article-title":"Gene therapy targeting hepatocellular carcinoma by a dual-regulated oncolytic adenovirus harboring the focal adhesion kinase shRNA","volume":"47","author":"Gao","year":"2015","journal-title":"Int J Oncol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"3236","DOI":"10.1038\/s41467-019-11137-5","article-title":"Molecular retargeting of antibodies converts immune defense against oncolytic viruses into cancer immunotherapy","volume":"10","author":"Niemann","year":"2019","journal-title":"Nat Commun"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1089\/cbr.2009.0752","article-title":"A novel oncolytic adenovirus expressing Escherichia coli cytosine deaminase exhibits potent antitumor effect on human solid tumors","volume":"25","author":"Zhang","year":"2010","journal-title":"Cancer Biother Radiopharm"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-67577-0_11","article-title":"Oncolytic Virotherapy and the Tumor Microenvironment","volume":"1036","author":"Berkey","year":"2017","journal-title":"Adv Exp Med Biol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.ebiom.2018.04.020","article-title":"Lighting a Fire in the Tumor Microenvironment Using Oncolytic Immunotherapy","volume":"31","author":"Achard","year":"2018","journal-title":"EBioMedicine"},{"key":"B18","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1002\/ijc.2910550118","article-title":"Interleukin-10 production by human carcinoma cell lines and its relationship to interleukin-6 expression","volume":"55","author":"Gastl","year":"1993","journal-title":"Int J Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1994.469","article-title":"Expression of interleukin 10 in human melanoma","volume":"70","author":"Kruger-Krasagakes","year":"1994","journal-title":"Br J Cancer"},{"key":"B20","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s10549-011-1855-x","article-title":"Role of interleukin-10 in breast cancer","volume":"133","author":"Hamidullah, Changkija","year":"2012","journal-title":"Breast Cancer Res Treat"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.11.5397","article-title":"Cutting edge: immune cells as sources and targets of the IL-10 family members","volume":"168","author":"Wolk","year":"2002","journal-title":"J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0139598","article-title":"Serum IL-10 Predicts Worse Outcome in Cancer Patients: A Meta-Analysis","volume":"10","author":"Zhao","year":"2015","journal-title":"PloS One"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.11.040193.001121","article-title":"Interleukin-10","volume":"11","author":"Moore","year":"1993","journal-title":"Annu Rev Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-0721","article-title":"IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs","volume":"72","author":"Emmerich","year":"2012","journal-title":"Cancer Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.1.384","article-title":"Anti-IL-10 therapeutic strategy using the immunomodulator AS101 in protecting mice from sepsis-induced death: dependence on timing of immunomodulating intervention","volume":"169","author":"Kalechman","year":"2002","journal-title":"J Immunol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/S0002-9440(10)63863-1","article-title":"CD4+ CD25+ regulatory T lymphocytes inhibit microbially induced colon cancer in Rag2-deficient mice","volume":"162","author":"Erdman","year":"2003","journal-title":"Am J Pathol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-011-8211-4","article-title":"Immunotherapeutic potential of oncolytic vaccinia virus","volume":"50","author":"Thorne","year":"2011","journal-title":"Immunol Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-0464","article-title":"A vaccinia virus armed with interleukin-10 is a promising therapeutic agent for treatment of murine pancreatic cancer","volume":"21","author":"Chard","year":"2015","journal-title":"Clin Cancer Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/0923-1811(92)90162-5","article-title":"Human IL-10 is a chemoattractant for CD8+ T lymphocytes and an inhibitor of IL-8-induced CD4+ T lymphocyte migration","volume":"151","author":"Jinquan","year":"1993","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1007\/s11434-011-4875-3","article-title":"CD8+ T cell response mediates the therapeutic effects of oncolytic adenovirus in an immunocompetent mouse model","volume":"57","author":"Yang","year":"2012","journal-title":"Chin Sci Bull"},{"key":"B31","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1007\/s12032-014-0352-6","article-title":"Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10\/STAT3\/bcl-2 signaling pathway","volume":"32","author":"Yang","year":"2015","journal-title":"Med Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118861","article-title":"CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice","volume":"63","author":"Erdman","year":"2003","journal-title":"Cancer Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118861","article-title":"Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses","volume":"98","author":"Berg","year":"1996","journal-title":"J Clin Invest"},{"key":"B34","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1006\/cimm.1997.1176","article-title":"Interleukin-10 inhibits tumor metastasis, downregulates MHC class I, and enhances NK lysis","volume":"180","author":"Kundu","year":"1997","journal-title":"Cell Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914500107","article-title":"IL-10 directly suppresses CD4 but not CD8 T cell effector and memory responses following acute viral infection","volume":"107","author":"Brooks","year":"2010","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.01.006","article-title":"Interleukin-10 Directly Inhibits CD8(+) T Cell Function by Enhancing N-Glycan Branching to Decrease Antigen Sensitivity","author":"Smith","year":"2018","journal-title":"Immunity"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2015.1048061","article-title":"Failure recovery of circulating NKG2D(+)CD56(dim)NK cells in HBV-associated hepatocellular carcinoma after hepatectomy predicts early recurrence","volume":"5","author":"Gao","year":"2016","journal-title":"Oncoimmunology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1553477","article-title":"Evaluating natural killer cell cytotoxicity against solid tumors using a microfluidic model","volume":"8","author":"Ayuso","year":"2019","journal-title":"Oncoimmunology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2018.1527498","article-title":"Circulating NKp46(+) Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer","volume":"8","author":"Picard","year":"2019","journal-title":"Oncoimmunology"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.615089\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T06:45:09Z","timestamp":1614321909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.615089\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,26]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2021.615089"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.615089","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,26]]},"article-number":"615089"}}