{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T13:18:11Z","timestamp":1781788691135,"version":"3.54.5"},"reference-count":52,"publisher":"Elsevier BV","issue":"5","license":[{"start":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T00:00:00Z","timestamp":1651363200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2022,5,1]],"date-time":"2022-05-01T00:00:00Z","timestamp":1651363200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","jhltonline.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Heart and Lung Transplantation"],"published-print":{"date-parts":[[2022,5]]},"DOI":"10.1016\/j.healun.2022.01.019","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T05:49:39Z","timestamp":1643608179000},"page":"568-577","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["Establishment of operational tolerance to sustain antitumor immunotherapy"],"prefix":"10.1016","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0264-2969","authenticated-orcid":false,"given":"Nana","family":"Dang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Waer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Sprangers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.healun.2022.01.019_bib0001","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1200\/JCO.2009.26.7609","article-title":"Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates","volume":"28","author":"Brahmer","year":"2010","journal-title":"J Clin Oncol"},{"key":"10.1016\/j.healun.2022.01.019_bib0002","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1056\/NEJMoa1305133","article-title":"Safety and tumor responses with lambrolizumab (anti-pd-1) in melanoma","volume":"369","author":"Hamid","year":"2013","journal-title":"N Engl J Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0003","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.clinthera.2015.02.018","article-title":"The next immune-checkpoint inhibitors: PD-1\/PD-L1 blockade in melanoma","volume":"37","author":"Mahoney","year":"2015","journal-title":"Clin Ther"},{"key":"10.1016\/j.healun.2022.01.019_bib0004","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.trre.2018.07.001","article-title":"Etiology of increased cancer incidence after solid organ transplantation","volume":"32","author":"Acuna","year":"2018","journal-title":"Transplant Rev (Orlando)"},{"key":"10.1016\/j.healun.2022.01.019_bib0005","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1056\/NEJMra022137","article-title":"Skin cancers after organ transplantation","volume":"348","author":"Euvrard","year":"2003","journal-title":"N Engl J Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0006","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1111\/ajt.14382","article-title":"Skin cancers in organ transplant recipients","volume":"17","author":"Mittal","year":"2017","journal-title":"Am J Transplant"},{"key":"10.1016\/j.healun.2022.01.019_bib0007","doi-asserted-by":"crossref","first-page":"e86434","DOI":"10.1172\/jci.insight.86434","article-title":"Cyclosporine A immunosuppression drives catastrophic squamous cell carcinoma through IL-22","volume":"1","author":"Abikhair","year":"2016","journal-title":"JCI Insight"},{"key":"10.1016\/j.healun.2022.01.019_bib0008","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1093\/ckj\/sfx122","article-title":"Risk factors associated with post- kidney transplant malignancies: an article from the Cancer-Kidney International Network","volume":"11","author":"Sprangers","year":"2018","journal-title":"Clin Kidney J"},{"key":"10.1016\/j.healun.2022.01.019_bib0009","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.3390\/ijms20092194","article-title":"Programmed cell death 1 (PD-1) inhibitors in renal transplant patients with advanced cancer: a double-edged sword?","volume":"20","author":"Lai","year":"2019","journal-title":"Int J Mol Sci"},{"key":"10.1016\/j.healun.2022.01.019_bib0010","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1111\/ajt.13786","article-title":"Use of the PD-1 pathway inhibitor nivolumab in a renal transplant patient with malignancy","volume":"16","author":"Boils","year":"2016","journal-title":"Am J Transplant"},{"key":"10.1016\/j.healun.2022.01.019_bib0011","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.kint.2020.12.015","article-title":"A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant","volume":"100","author":"Murakami","year":"2021","journal-title":"Kidney Int"},{"key":"10.1016\/j.healun.2022.01.019_bib0012","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/ajt.16105","article-title":"Intratumoral immunotherapy with anti-PD-1 and TLR9 agonist induces systemic antitumor immunity without accelerating rejection of cardiac allografts","volume":"21","author":"Dang","year":"2021","journal-title":"Am J Transplant"},{"key":"10.1016\/j.healun.2022.01.019_bib0013","doi-asserted-by":"crossref","first-page":"270","DOI":"10.2337\/diabetes.50.2.270","article-title":"Prolonged islet graft survival in NOD mice by blockade of the CD40-CD154 pathway of T-cell co-stimulation","volume":"50","author":"Molano","year":"2001","journal-title":"Diabetes"},{"key":"10.1016\/j.healun.2022.01.019_bib0014","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/9536","article-title":"Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates","volume":"5","author":"Kirk","year":"1999","journal-title":"Nat Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0015","doi-asserted-by":"crossref","first-page":"6705","DOI":"10.1021\/acs.jmedchem.8b00521","article-title":"Discovery of a potent, orally bioavailable PI4KIII\u03b2 Inhibitor (UCB9608) able to significantly prolong allogeneic organ engraftment in vivo","volume":"61","author":"Reuberson","year":"2018","journal-title":"J Med Chem"},{"key":"10.1016\/j.healun.2022.01.019_bib0016","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.healun.2004.06.008","article-title":"Inhibition of obliterative airway disease development following heterotopic murine tracheal transplantation by costimulatory molecule blockade using anti-CD40 ligand alone or in combination with donor bone marrow","volume":"24","author":"Fern\u00e1ndez","year":"2005","journal-title":"J Hear Lung Transplant"},{"key":"10.1016\/j.healun.2022.01.019_bib0017","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nm965","article-title":"Homeostatic proliferation is a barrier to transplantation tolerance","volume":"10","author":"Wu","year":"2004","journal-title":"Nat Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0018","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1084\/jem.141.2.360","article-title":"Evidence for a B-cell-like helper function in mixed lymphocyte culture between immunocompetent thymus cells","volume":"141","author":"Kyminski","year":"1975","journal-title":"J Exp Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0019","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1158\/0008-5472.CAN-18-3143","article-title":"Solid tumor-induced immune regulation alters the GvHD\/GvT paradigm after allogenic bone marrow transplantation","volume":"79","author":"Dang","year":"2019","journal-title":"Cancer Res"},{"key":"10.1016\/j.healun.2022.01.019_bib0020","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.3390\/cancers11111694","article-title":"Improved anti-tumour adaptive immunity can overcome the melanoma immunosuppressive tumor microenvironment","volume":"11","author":"Dang","year":"2019","journal-title":"Cancers (Basel)"},{"key":"10.1016\/j.healun.2022.01.019_bib0021","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1158\/2326-6066.CIR-19-0666","article-title":"Donor lymphocyte-derived natural killer cells control major histocompatibility complex class I-negative melanoma","volume":"8","author":"Dang","year":"2020","journal-title":"Cancer Immunol Res"},{"key":"10.1016\/j.healun.2022.01.019_bib0022","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.canlet.2021.01.027","article-title":"Immunization with alloantibodies-covered melanoma cells induces regional antitumor effects that become systemic when combined with 5-FU treatment","volume":"503","author":"Dang","year":"2021","journal-title":"Cancer Lett"},{"key":"10.1016\/j.healun.2022.01.019_bib0023","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.139331","article-title":"Kidney-induced systemic tolerance of heart allografts in mice","volume":"5","author":"Yang","year":"2020","journal-title":"JCI Insight"},{"key":"10.1016\/j.healun.2022.01.019_bib0024","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1111\/ajt.13489","article-title":"Effects of lung cotransplantation on cardiac allograft tolerance across a full major histocompatibility complex barrier in miniature swine","volume":"16","author":"Madariaga","year":"2016","journal-title":"Am J Transplant"},{"key":"10.1016\/j.healun.2022.01.019_bib0025","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.lungcan.2016.10.008","article-title":"Corneal graft rejection in a patient treated with nivolumab for primary lung cancer","volume":"102","author":"Le Fournis","year":"2016","journal-title":"Lung Cancer"},{"key":"10.1016\/j.healun.2022.01.019_bib0026","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.det.2011.02.004","article-title":"Management of skin cancer in solid-organ transplant recipients: a multidisciplinary approach","volume":"29","author":"Greenberg","year":"2011","journal-title":"Dermatol Clin"},{"key":"10.1016\/j.healun.2022.01.019_bib0027","doi-asserted-by":"crossref","first-page":"512","DOI":"10.4049\/jimmunol.164.1.512","article-title":"Treatment of allograft recipients with donor-specific transfusion and anti-CD154 antibody leads to deletion of alloreactive CD8+ T cells and prolonged graft survival in a CTLA4-dependent manner","volume":"164","author":"Iwakoshi","year":"2000","journal-title":"J Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0028","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/15260","article-title":"Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance","volume":"5","author":"Wells","year":"1999","journal-title":"Nat Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0029","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41591-020-1131-x","article-title":"Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination","volume":"27","author":"Yu","year":"2021","journal-title":"Nat Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0030","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1038\/s41591-018-0135-2","article-title":"Sequestration of T cells in bone marrow in the setting of glioblastoma and other intracranial tumors","volume":"24","author":"Chongsathidkiet","year":"2018","journal-title":"Nat Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0031","doi-asserted-by":"crossref","first-page":"973","DOI":"10.4049\/jimmunol.166.2.973","article-title":"Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question","volume":"166","author":"Suchin","year":"2001","journal-title":"J Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0032","doi-asserted-by":"crossref","first-page":"e97219","DOI":"10.1172\/jci.insight.97219","article-title":"Unique features and clinical importance of acute alloreactive immune responses","volume":"17","author":"Inman","year":"2018","journal-title":"JCI Insight"},{"key":"10.1016\/j.healun.2022.01.019_bib0033","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1074-7613(00)80177-6","article-title":"The relationship of MHC-peptide binding and T cell activation probed using chemically defined MHC class II oligomers","volume":"12","author":"Cochran","year":"2000","journal-title":"Immunity"},{"key":"10.1016\/j.healun.2022.01.019_bib0034","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.immuni.2016.01.018","article-title":"Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses","volume":"44","author":"Taylor","year":"2016","journal-title":"Immunity"},{"key":"10.1016\/j.healun.2022.01.019_bib0035","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.immuni.2013.01.004","article-title":"Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy","volume":"38","author":"Liao","year":"2013","journal-title":"Immunity"},{"key":"10.1016\/j.healun.2022.01.019_bib0036","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/nm.3286","article-title":"Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity","volume":"19","author":"Liu","year":"2013","journal-title":"Nat Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0037","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1016\/j.immuni.2015.05.016","article-title":"E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1 to maintain regulatory T cell stability and suppressive capacity","volume":"42","author":"Lee","year":"2015","journal-title":"Immunity"},{"key":"10.1016\/j.healun.2022.01.019_bib0038","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0025-6196(12)65097-6","article-title":"Cyclosporine nephrotoxicity is minimized by adjusting dosage on the basis of drug concentration in blood","volume":"63","author":"Moyer","year":"1988","journal-title":"Mayo Clin Proc"},{"key":"10.1016\/j.healun.2022.01.019_bib0039","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev.iy.03.040185.002145","article-title":"The effects of cyclosporin A on the immune system","volume":"3","author":"Shevach","year":"1985","journal-title":"Ann Rev Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0040","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1186\/s40425-019-0811-x","article-title":"TLR9 activation cooperates with T cell checkpoint blockade to regress poorly immunogenic melanoma","volume":"7","author":"Reilley","year":"2019","journal-title":"J Immunother Cancer"},{"key":"10.1016\/j.healun.2022.01.019_bib0041","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/0167-5699(94)90269-0","article-title":"The role of CD40 in the regulation of humoral and cell-mediated immunity","volume":"15","author":"Durie","year":"1994","journal-title":"Immunol Today"},{"key":"10.1016\/j.healun.2022.01.019_bib0042","doi-asserted-by":"crossref","first-page":"4983","DOI":"10.4049\/jimmunol.162.8.4983","article-title":"CTLA4 signals are required to optimally induce allograft tolerance with combined donor-specific transfusion and anti-CD154 monoclonal antibody treatment","volume":"162","author":"Zheng","year":"1999","journal-title":"J Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0043","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.2337\/diabetes.48.7.1473","article-title":"Long-term survival and unction of intrahepatic islet allografts in baboons treated with humanized anti-CD154","volume":"48","author":"Kenyon","year":"1999","journal-title":"Diabetes"},{"key":"10.1016\/j.healun.2022.01.019_bib0044","doi-asserted-by":"crossref","first-page":"3983","DOI":"10.4049\/jimmunol.172.7.3983","article-title":"IL-2, regulatory T cells, and tolerance","volume":"172","author":"Nelson","year":"2004","journal-title":"J Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0045","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/nm.2155","article-title":"In vivo tracking of \u2018color-coded\u2019 effector, natural and induced regulatory T cells in the allograft response","volume":"16","author":"Fan","year":"2010","journal-title":"Nat Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0046","doi-asserted-by":"crossref","first-page":"3947","DOI":"10.4049\/jimmunol.1200449","article-title":"Foxp3 expression is required for the induction of therapeutic tissue tolerance","volume":"189","author":"Regateiro","year":"2012","journal-title":"J Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0047","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/ni853","article-title":"Dominant transplantation tolerance impairs CD8+ T cell function but not expansion","volume":"3","author":"Lin","year":"2002","journal-title":"Nat Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0048","doi-asserted-by":"crossref","first-page":"5558","DOI":"10.4049\/jimmunol.168.11.5558","article-title":"Both CD4(+)CD25(+) and CD4(+)CD25(-) regulatory cells mediate dominant transplantation tolerance","volume":"168","author":"Graca","year":"2002","journal-title":"J Immunol"},{"key":"10.1016\/j.healun.2022.01.019_bib0049","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/S1470-2045(19)30388-2","article-title":"Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study","volume":"20","author":"Robert","year":"2019","journal-title":"Lancet Oncol"},{"key":"10.1016\/j.healun.2022.01.019_bib0050","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-year survival with combined Nivolumab and Ipilimumab in advanced melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"N Eng J Med"},{"key":"10.1016\/j.healun.2022.01.019_bib0051","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"10.1016\/j.healun.2022.01.019_bib0052","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1634\/theoncologist.2018-0195","article-title":"Immune checkpoint inhibitors and the risk of allograft rejection: a comprehensive analysis on an emerging issue","volume":"24","author":"Aguirre","year":"2019","journal-title":"Oncologist"}],"container-title":["The Journal of Heart and Lung Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1053249822000377?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1053249822000377?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T15:14:13Z","timestamp":1762355653000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1053249822000377"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5]]},"references-count":52,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2022,5]]}},"alternative-id":["S1053249822000377"],"URL":"https:\/\/doi.org\/10.1016\/j.healun.2022.01.019","relation":{},"ISSN":["1053-2498"],"issn-type":[{"value":"1053-2498","type":"print"}],"subject":[],"published":{"date-parts":[[2022,5]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Establishment of operational tolerance to sustain antitumor immunotherapy","name":"articletitle","label":"Article Title"},{"value":"The Journal of Heart and Lung Transplantation","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.healun.2022.01.019","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2022 International Society for Heart and Lung Transplantation. All rights reserved.","name":"copyright","label":"Copyright"}]}}