{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T02:02:37Z","timestamp":1787623357217,"version":"build-2736575974"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T00:00:00Z","timestamp":1543536000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"DOI":"10.3389\/fmed.2018.00337","type":"journal-article","created":{"date-parts":[[2018,11,30]],"date-time":"2018-11-30T04:52:06Z","timestamp":1543553526000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The Regulatory Status Adopted by Lymph Node Dendritic Cells and T Cells During Healthy Aging Is Maintained During Cancer and May Contribute to Reduced Responses to Immunotherapy"],"prefix":"10.3389","volume":"5","author":[{"given":"Joanne K.","family":"Gardner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie","family":"Jackaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril D. S.","family":"Mamotte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delia J.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2018,11,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1007\/s12307-012-0127-6","article-title":"Effector CD4 and CD8 T cells and their role in the tumor microenvironment","volume":"6","author":"Hadrup","year":"2013","journal-title":"Cancer Microenviron."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e26403","DOI":"10.4161\/onci.26403","article-title":"Antitumor immune responses mediated by dendritic cells: how signals derived from dying cancer cells drive antigen cross-presentation","volume":"2","author":"Spel","year":"2013","journal-title":"Oncoimmunology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/nrc3258","article-title":"Cancer immunotherapy via dendritic cells","volume":"12","author":"Palucka","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"B4","doi-asserted-by":"publisher","first-page":"539519","DOI":"10.1155\/2010\/539519","article-title":"Tumor antigen cross-presentation and the dendritic cell: Where it all begins?","volume":"2010","author":"McDonnell","year":"2010","journal-title":"Clin Dev Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.immuni.2008.08.004","article-title":"Cancer immunotherapy by dendritic cells","volume":"29","author":"Melief","year":"2008","journal-title":"Immunity"},{"key":"B6","doi-asserted-by":"publisher","first-page":"6341","DOI":"10.1158\/0008-5472.can-07-5769","article-title":"Impaired dendritic cell function in aging leads to defective antitumor immunity","volume":"68","author":"Grolleau-Julius","year":"2008","journal-title":"Cancer Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1093\/gerona\/61.10.1039","article-title":"Effect of aging on bone marrow-derived murine CD11c+CD4\u2013CD8\u03b1- dendritic cell function","volume":"61","author":"Grolleau-Julius","year":"2006","journal-title":"J Gerontol A Biol Sci Med Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.exger.2005.10.002","article-title":"Aging affect the anti-tumor potential of dendritic cell vaccination, but it can be overcome by co-stimulation with anti-OX40 or anti-4-1BB","volume":"41","author":"Sharma","year":"2006","journal-title":"Exp Gerontol."},{"key":"B9","first-page":"125","article-title":"Increased susceptibility of tumorigenicity and decreased anti-tumor effect of DC vaccination in aged mice are potentially associated with increased number of NK1","volume":"27","author":"Shi","year":"2005","journal-title":"Exp Oncol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.mad.2008.05.003","article-title":"Cancer vaccination: manipulation of immune responses at old age","volume":"130","author":"Gravekamp","year":"2009","journal-title":"Mech Age Dev."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.4049\/jimmunol.182.3.1481","article-title":"OX40-enhanced tumor rejection and effector T cell differentiation decreases with age","volume":"182","author":"Ruby","year":"2009","journal-title":"J Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/S0264-410X(02)00530-3","article-title":"Low effectiveness of DNA vaccination against HER-2\/neu in ageing","volume":"21","author":"Provinciali","year":"2003","journal-title":"Vaccine"},{"key":"B13","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/j.1348-0421.2002.tb02728.x","article-title":"Immune responses against allogeneic and syngeneic tumors in aged C57BL\/6 mice","volume":"46","author":"Win","year":"2002","journal-title":"Microbiol Immunol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1007\/s002620100203","article-title":"Impact of aging on immune modulation by tumor","volume":"50","author":"Young","year":"2001","journal-title":"Cancer Immunol Immunother."},{"key":"B15","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/sj.gt.3301131","article-title":"Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered to release IL-2 are rejected but do not induce tumor specific immune memory in old mice","volume":"7","author":"Provinciali","year":"2000","journal-title":"Gene Ther."},{"key":"B16","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1097\/00002371-199807000-00008","article-title":"Loss of resistance to a highly immunogenic tumor with age corresponds to the decline of CD8 T cell activity","volume":"21","author":"Flood","year":"1998","journal-title":"J Immunother."},{"key":"B17","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1084\/jem.154.2.275","article-title":"Loss of tumor-specific and idiotype-specific immunity with age","volume":"154","author":"Flood","year":"1981","journal-title":"J Exp Med."},{"key":"B18","doi-asserted-by":"crossref","first-page":"527","DOI":"10.4049\/jimmunol.133.1.527","article-title":"Rescue of the tumor-specific immune response of aged mice in vitro","volume":"133","author":"Urban","year":"1984","journal-title":"J Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"491","DOI":"10.3978\/j.issn.2225-319X.2012.11.04","article-title":"Malignant pleural mesothelioma: an epidemiological perspective","volume":"1","author":"Robinson","year":"2012","journal-title":"Ann Cardiothorac Surg."},{"key":"B20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.4161\/cam.4.1.11361","article-title":"What's the place of immunotherapy in malignant mesothelioma treatments?","volume":"4","author":"Gr\u00e9goire","year":"2010","journal-title":"Cell Adhesion Migrat."},{"key":"B21","doi-asserted-by":"publisher","first-page":"2089","DOI":"10.1158\/0008-5472.can-11-3019","article-title":"Mitigating age-related immune dysfunction heightens the efficacy of tumor immunotherapy in aged mice","volume":"72","author":"Hurez","year":"2012","journal-title":"Cancer Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1007\/s00262-007-0393-1","article-title":"CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged","volume":"57","author":"Sharma","year":"2008","journal-title":"Cancer Immunol Immunother."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4510","DOI":"10.4049\/jimmunol.173.7.4510","article-title":"Aged mice develop protective antitumor immune responses with appropriate costimulation","volume":"173","author":"Lustgarten","year":"2004","journal-title":"J Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"873","DOI":"10.2217\/fon.10.64","article-title":"Cancer immunotherapy: focusing on the young, neglecting the old","volume":"6","author":"Lustgarten","year":"2010","journal-title":"Future Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1979","DOI":"10.1007\/s00262-009-0677-8","article-title":"Cancer, aging and immunotherapy: lessons learned from animal models","volume":"58","author":"Lustgarten","year":"2009","journal-title":"Cancer Immunol Immunother."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1093\/intimm\/dxn104","article-title":"Deliberately provoking local inflammation drives tumors to become their own protective vaccine site","volume":"20","author":"Jackaman","year":"2008","journal-title":"Int Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/icb.2010.88","article-title":"CD40-activated B cells contribute to mesothelioma tumor regression","volume":"89","author":"Jackaman","year":"2011","journal-title":"Immunol Cell Biol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"e1173299","DOI":"10.1080\/2162402X.2016.1173299","article-title":"Murine mesothelioma induces locally-proliferating IL-10+TNF-\u03b1+CD206\u2013CX3CR1+ M3 macrophages that can be selectively depleted by chemotherapy or immunotherapy","volume":"5","author":"Jackaman","year":"2016","journal-title":"OncoImmunology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1007\/s00262-011-1120-5","article-title":"Intratumoral interleukin-2\/agonist CD40 antibody drives CD4+ -independent resolution of treated-tumors and CD4+ -dependent systemic and memory responses","volume":"61","author":"Jackaman","year":"2012","journal-title":"Cancer Immunol Immunother."},{"key":"B30","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1093\/intimm\/dxs005","article-title":"IL-2\/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector\/memory phase","volume":"24","author":"Jackaman","year":"2012","journal-title":"Int Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"9655","DOI":"10.1007\/s11357-014-9655-y","article-title":"IL-2\/CD40-activated macrophages rescue age and tumor-induced T cell dysfunction in elderly mice","volume":"36","author":"Jackaman","year":"2014","journal-title":"Age"},{"key":"B32","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1111\/acel.12062","article-title":"Targeting macrophages rescues age-related immune deficiencies in C57BL\/6J geriatric mice","volume":"12","author":"Jackaman","year":"2013","journal-title":"Aging Cell"},{"key":"B33","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1111\/j.1474-9726.2009.00478.x","article-title":"Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels","volume":"8","author":"Yuan","year":"2009","journal-title":"Aging Cell"},{"key":"B34","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1007\/s10522-009-9260-0","article-title":"Delayed but excellent myogenic stem cell response of regenerating geriatric skeletal muscles in mice","volume":"11","author":"Shavlakadze","year":"2010","journal-title":"Biogerontology"},{"key":"B35","doi-asserted-by":"publisher","first-page":"5051","DOI":"10.4049\/jimmunol.171.10.5051","article-title":"IL-2 intratumoral immunotherapy enhances CD8+ T cells that mediate destruction of tumor cells and tumor-associated vasculature: a novel mechanism for IL-2","volume":"171","author":"Jackaman","year":"2003","journal-title":"J Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"526","DOI":"10.3389\/fgene.2018.00526","article-title":"Macrophage Depletion in Elderly Mice Improves Response to Tumor Immunotherapy, Increases Anti-tumor T Cell Activity and Reduces Treatment-Induced Cachexia","volume":"9","author":"Duong","year":"2018","journal-title":"Front Genet"},{"key":"B37","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1189\/jlb.0812397","article-title":"Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive\/tolerogenic cells: insight into the molecular mechanisms","volume":"93","author":"Demoulin","year":"2013","journal-title":"J Leuk Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.immuni.2005.03.013","article-title":"GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase","volume":"22","author":"Munn","year":"2005","journal-title":"Immunity"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1182\/blood-2009-07-235382","article-title":"Granzyme B produced by human plasmacytoid dendritic cells suppresses T-cell expansion","volume":"115","author":"Jahrsdorfer","year":"2010","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.1172\/JCI31911","article-title":"Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase","volume":"117","author":"Sharma","year":"2007","journal-title":"J Clin Invest."},{"key":"B41","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1172\/JCI200421583","article-title":"Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic cells in tumor-draining lymph nodes","volume":"114","author":"Munn","year":"2004","journal-title":"J Clin Invest."},{"key":"B42","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1093\/intimm\/dxs103","article-title":"Plasmacytoid dendritic cells have a cytokine-producing capacity to enhance ICOS ligand-mediated IL-10 production during T-cell priming","volume":"25","author":"Ogata","year":"2013","journal-title":"Int Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"5240","DOI":"10.1158\/0008-5472.can-12-2271","article-title":"Plasmacytoid dendritic cells promote immunosuppression in ovarian cancer via ICOS costimulation of Foxp3+ T-regulatory cells","volume":"72","author":"Conrad","year":"2012","journal-title":"Cancer Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"6130","DOI":"10.1158\/0008-5472.can-12-2409","article-title":"ICOS-ligand expression on plasmacytoid dendritic cells supports breast cancer progression by promoting the accumulation of immunosuppressive CD4+ T cells","volume":"72","author":"Faget","year":"2012","journal-title":"Cancer Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1084\/jem.20061660","article-title":"Plasmacytoid dendritic cells prime IL-10\u2013producing T regulatory cells by inducible costimulator ligand","volume":"204","author":"Ito","year":"2007","journal-title":"J Exp Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1111\/j.1600-065X.2006.00444.x","article-title":"The tumor-draining lymph node as an immune-privileged site","volume":"213","author":"Munn","year":"2006","journal-title":"Immunol Rev."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1586\/era.12.147","article-title":"Breast cancer immunobiology driving immunotherapy: vaccines and immune checkpoint blockade","volume":"12","author":"Emens","year":"2012","journal-title":"Expert Rev Anticancer Ther."},{"key":"B48","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.it.2009.03.013","article-title":"CD28- T cells: their role in the age-associated decline of immune function","volume":"30","author":"Weng","year":"2009","journal-title":"Trends Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"3543","DOI":"10.1182\/blood-2002-08-2574","article-title":"CD28 loss in senescent CD4+ T cells: reversal by interleukin-12 stimulation","volume":"101","author":"Warrington","year":"2003","journal-title":"Blood"},{"key":"B50","doi-asserted-by":"crossref","first-page":"8119","DOI":"10.1074\/jbc.273.14.8119","article-title":"Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity","volume":"273","author":"Vallejo","year":"1998","journal-title":"J Biol Chem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/S0145-305X(97)00027-X","article-title":"Loss of CD28 expression on T lymphocytes: A marker of replicative senescence","volume":"21","author":"Effros","year":"1997","journal-title":"Dev Comp Immunol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.mad.2009.08.006","article-title":"Advancing age leads to predominance of inhibitory receptor expressing CD4 T cells","volume":"130","author":"Channappanavar","year":"2009","journal-title":"Mech Ageing Dev."},{"key":"B53","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.exger.2009.05.003","article-title":"Age-associated up-regulation of a negative co-stimulatory receptor PD-1 in mouse CD4+ T cells","volume":"44","author":"Shimada","year":"2009","journal-title":"Exp Gerontol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1084\/jem.182.2.459","article-title":"CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation","volume":"182","author":"Krummel","year":"1995","journal-title":"J Exp Med."},{"key":"B55","doi-asserted-by":"publisher","first-page":"3567","DOI":"10.1016\/j.molimm.2008.05.014","article-title":"Interaction of human PD-L1 and B7-1","volume":"45","author":"Butte","year":"2008","journal-title":"Mol Immunol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.immuni.2007.05.016","article-title":"Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses","volume":"27","author":"Butte","year":"2007","journal-title":"Immunity"},{"key":"B57","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1111\/j.1474-9726.2010.00611.x","article-title":"Partial restoration of T-cell function in aged mice by in vitro blockade of the PD-1\/ PD-L1 pathway","volume":"9","author":"Lages","year":"2010","journal-title":"Aging Cell"},{"key":"B58","doi-asserted-by":"publisher","first-page":"5466","DOI":"10.4049\/jimmunol.0903561","article-title":"B7-H1 expression on old CD8+ T cells negatively regulates the activation of immune responses in aged animals","volume":"184","author":"Mirza","year":"2010","journal-title":"J Immunol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1111\/acel.12435","article-title":"Characterization of age-associated exhausted CD8(+) T cells defined by increased expression of Tim-3 and PD-1","volume":"15","author":"Lee","year":"2016","journal-title":"Aging Cell"},{"key":"B60","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1182\/blood-2015-02-626754","article-title":"Mechanisms of PD-L1\/PD-1\u2013mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the E\u03bc-TCL1 CLL mouse model","volume":"126","author":"McClanahan","year":"2015","journal-title":"Blood"},{"key":"B61","doi-asserted-by":"publisher","first-page":"e84728","DOI":"10.1371\/journal.pone.0084728","article-title":"C\/EBP\u03b1 is dispensable for the ontogeny of PD-1+ CD4+ memory T cells but restricts their expansion in an age-dependent manner","volume":"9","author":"Norrie","year":"2014","journal-title":"PLoS ONE"},{"key":"B62","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.4049\/jimmunol.1101098","article-title":"Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors","volume":"188","author":"Decman","year":"2012","journal-title":"J Immunol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"15807","DOI":"10.1073\/pnas.0908805106","article-title":"PD-1+ memory phenotype CD4+ T cells expressing C\/EBPalpha underlie T cell immunodepression in senescence and leukemia","volume":"106","author":"Shimatani","year":"2009","journal-title":"Proc Natl Acad Sci USA."},{"key":"B64","doi-asserted-by":"publisher","first-page":"6692","DOI":"10.1038\/ncomms7692","article-title":"PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation","volume":"6","author":"Patsoukis","year":"2015","journal-title":"Nat Commun."},{"key":"B65","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1111\/j.1600-065X.2010.00923.x","article-title":"The PD-1 pathway in tolerance and autoimmunity","volume":"236","author":"Francisco","year":"2010","journal-title":"Immunol Rev."},{"key":"B66","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/j.1600-065X.2009.00767.x","article-title":"PD-1 signaling in primary T cells","volume":"229","author":"Riley","year":"2009","journal-title":"Immunol Rev."},{"key":"B67","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1002\/1521-4141(200203)32:3<634::AID-IMMU634>3.0.CO;2-9","article-title":"PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2","volume":"32","author":"Carter","year":"2002","journal-title":"Eur J Immunol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"688","DOI":"10.4049\/jimmunol.174.2.688","article-title":"Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223)","volume":"174","author":"Workman","year":"2005","journal-title":"J Immunol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1189\/jlb.1A0114-066R","article-title":"Early-onset age-related changes in dendritic cell subsets can impair antigen-specific T helper 1 (Th1) CD4 T cell priming","volume":"96","author":"Farazi","year":"2014","journal-title":"J Leukocyte Biol."},{"key":"B70","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.mad.2011.03.005","article-title":"Impaired in vivo CD4+ T cell expansion and differentiation in aged mice is not solely due to T cell defects: decreased stimulation by aged dendritic cells","volume":"132","author":"Pereira","year":"2011","journal-title":"Mech Age Dev."},{"key":"B71","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.molmed.2013.03.005","article-title":"CD39 and CD73 in immunity and inflammation","volume":"19","author":"Antonioli","year":"2013","journal-title":"Trends Mol Med."},{"key":"B72","doi-asserted-by":"publisher","first-page":"932","DOI":"10.4049\/jimmunol.173.2.932","article-title":"Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases","volume":"173","author":"Zhang","year":"2004","journal-title":"J Immunol."},{"key":"B73","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1242\/jcs.112.4.491","article-title":"Expression of A2B adenosine receptors in human lymphocytes: their role in T cell activation","volume":"112","author":"Mirabet","year":"1999","journal-title":"J Cell Sci."},{"key":"B74","doi-asserted-by":"publisher","first-page":"e32416","DOI":"10.1371\/journal.pone.0032416","article-title":"Adora2b adenosine receptor engagement enhances regulatory T cell abundance during endotoxin-induced pulmonary inflammation","volume":"7","author":"Ehrentraut","year":"2012","journal-title":"PLoS ONE"},{"key":"B75","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.bbrc.2011.04.125","article-title":"Adenosine A2B receptor antagonist suppresses differentiation to regulatory T cells without suppressing activation of T cells","volume":"409","author":"Nakatsukasa","year":"2011","journal-title":"Biochem Biophys Res Commun."},{"key":"B76","doi-asserted-by":"publisher","first-page":"R130","DOI":"10.1186\/cc13941","article-title":"Persistent inflammation and T cell exhaustion in severe sepsis in the elderly","volume":"18","author":"Inoue","year":"2014","journal-title":"Crit Care"},{"key":"B77","unstructured":"GardnerJK Curtin UniversityAn Increase in Suppressive Dendritic Cells and T Cells is a Hallmark of Healthy Aging, A Phenomenon Exacerbated by Cancer and Modulated by Chemo- and Immunotherapy2016"},{"key":"B78","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol."},{"key":"B79","doi-asserted-by":"publisher","first-page":"e1005177","DOI":"10.1371\/journal.ppat.1005177","article-title":"CD39 expression identifies terminally exhausted CD8+ T cells","volume":"11","author":"Gupta","year":"2015","journal-title":"PLoS Pathog."},{"key":"B80","doi-asserted-by":"publisher","first-page":"e1792","DOI":"10.1038\/cddis.2015.162","article-title":"T-cell exhaustion in the tumor microenvironment","volume":"6","author":"Jiang","year":"2015","journal-title":"Cell Death Dis."},{"key":"B81","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1172\/JCI46102","article-title":"Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients","volume":"121","author":"Baitsch","year":"2011","journal-title":"J Clin Invest."},{"key":"B82","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1084\/jem.20100643","article-title":"Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity","volume":"207","author":"Sakuishi","year":"2010","journal-title":"J Exp Med."},{"key":"B83","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and cellular insights into T cell exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat Rev Immunol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"5327","DOI":"10.4049\/jimmunol.166.9.5327","article-title":"Intravenous soluble antigen is presented to CD4 T cells by CD8- dendritic cells but cross-presented to CD8 T cells by CD8+ dendritic cells","volume":"166","author":"Pooley","year":"2001","journal-title":"J Immunol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1084\/jem.189.3.587","article-title":"CD8\u03b1+ and CD8\u03b1- subclasses of dendritic cells direct the development of distinct T helper cells in vivo","volume":"189","author":"Maldonado-Lopez","year":"1999","journal-title":"J Exp Med."},{"key":"B86","doi-asserted-by":"publisher","first-page":"3665","DOI":"10.4049\/jimmunol.1402898","article-title":"IL-10 potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1","volume":"195","author":"Hsu","year":"2015","journal-title":"J Immunol."},{"key":"B87","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/90667","article-title":"Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen","volume":"2","author":"Akbari","year":"2001","journal-title":"Nat Immunol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1038\/ni.3399","article-title":"Tumor-necrosis factor impairs CD4+ T cell-mediated immunological control in chronic viral infection","volume":"17","author":"Beyer","year":"2016","journal-title":"Nat Immunol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"19455","DOI":"10.1073\/pnas.0909474106","article-title":"Successful immunotherapy with IL-2\/anti-CD40 induces the chemokine-mediated mitigation of an immunosuppressive tumor microenvironment","volume":"106","author":"Weiss","year":"2009","journal-title":"Proc Natl Acad Sci USA."},{"key":"B90","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1038\/nm1554","article-title":"IFN-gamma mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy","volume":"13","author":"Berner","year":"2007","journal-title":"Nat Med."},{"key":"B91","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.bbmt.2004.05.006","article-title":"Tumor regression by anti-CD40 and interleukin-2: role of CD40 in hematopoietic cells and organ-specific effects","volume":"10","author":"Welniak","year":"2004","journal-title":"Biol Blood Bone Marrow Trans."},{"key":"B92","doi-asserted-by":"publisher","first-page":"2727","DOI":"10.4049\/jimmunol.170.5.2727","article-title":"Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses","volume":"170","author":"Murphy","year":"2003","journal-title":"J Immunol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"5821","DOI":"10.4049\/jimmunol.1400404","article-title":"Regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment undergo Fas-dependent cell death during IL-2\/\u03b1CD40 therapy","volume":"192","author":"Weiss","year":"2014","journal-title":"J Immunol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"2270","DOI":"10.1158\/1078-0432.ccr-10-2888","article-title":"Local activation of CD8 T cells and systemic tumor eradication without toxicity via slow release and local delivery of agonistic CD40 antibody","volume":"17","author":"Fransen","year":"2011","journal-title":"Clin Cancer Res."},{"key":"B95","doi-asserted-by":"publisher","first-page":"5923","DOI":"10.4049\/jimmunol.173.10.5923","article-title":"Cutting edge: Tumor-specific CTL are constitutively cross-armed in draining lymph nodes and transiently disseminate to mediate tumor regression following systemic CD40 activation","volume":"173","author":"Stumbles","year":"2004","journal-title":"J Immunol."},{"key":"B96","doi-asserted-by":"publisher","first-page":"4616","DOI":"10.4049\/jimmunol.0801279","article-title":"The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells","volume":"182","author":"Wilson","year":"2009","journal-title":"J Immunol."},{"key":"B97","doi-asserted-by":"publisher","first-page":"1610","DOI":"10.1002\/eji.200737781","article-title":"Modulation of murine dendritic cell function by adenine nucleotides and adenosine: involvement of the A(2B) receptor","volume":"38","author":"Addi","year":"2008","journal-title":"Eur J Immunol."},{"key":"B98","doi-asserted-by":"publisher","first-page":"1822","DOI":"10.1182\/blood-2008-02-136325","article-title":"Adenosine receptors in regulation of dendritic cell differentiation and function","volume":"112","author":"Novitskiy","year":"2008","journal-title":"Blood"},{"key":"B99","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/2045-3701-1-20","article-title":"Role of dendritic cells in the induction of regulatory T cells","volume":"1","author":"Kushwah","year":"2011","journal-title":"Cell Biosci."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1757","DOI":"10.1084\/jem.20070590","article-title":"A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism","volume":"204","author":"Coombes","year":"2007","journal-title":"J Exp Med."},{"key":"B101","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1080\/14712598.2017.1294157","article-title":"The role of checkpoint inhibitors immunotherapy in advanced non-small cell lung cancer in the elderly","volume":"17","author":"Sgambato","year":"2017","journal-title":"Expert Opin Biol Ther."},{"key":"B102","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1756-9966-33-30","article-title":"Efficacy and safety of ipilimumab in elderly patients with pretreated advanced melanoma treated at Italian centres through the expanded access programme","volume":"33","author":"Chiarion Sileni","year":"2014","journal-title":"J Exp Clin Cancer Res."},{"key":"B103","doi-asserted-by":"publisher","first-page":"P133","DOI":"10.1186\/2051-1426-3-S2-P133","article-title":"Subset analysis of the safety and efficacy of nivolumab in elderly patients with metastatic melanoma","volume":"3","author":"Freeman","year":"2015","journal-title":"J Immunother Cancer"},{"key":"B104","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.ctrv.2016.02.006","article-title":"Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis","volume":"45","author":"Nishijima","year":"2016","journal-title":"Cancer Treat Rev."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fmed.2018.00337\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T19:08:12Z","timestamp":1694113692000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fmed.2018.00337\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,30]]},"references-count":104,"alternative-id":["10.3389\/fmed.2018.00337"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2018.00337","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,30]]},"article-number":"337"}}