{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T03:23:36Z","timestamp":1789442616425,"version":"build-2803163510"},"reference-count":42,"publisher":"American Society of Hematology","issue":"23","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,4]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>The significance of endogenous immune surveillance in acute lymphoblastic leukemia (ALL) remains controversial. Using clinical B-cell ALL samples and a novel mouse model, we show that neoantigen-specific CD4+ T cells are induced to adopt type 1 regulatory (Tr1) function in the leukemia microenvironment. Tr1 cells then inhibit cytotoxic CD8+ T cells, preventing effective leukemia clearance. Leukemic cells induce Tr1 cells by phenocopying hematopoietic stem cells, which normally are subject to effective surveillance by this CD4+ subset. This mechanism effectively redirects Tr1 cells from a role in preventing cancer to maladaptively promoting clinical relapse. In mouse models, addition of interleukin-10 receptor (IL-10R) blockade to cytotoxic therapy modestly affected Tr1 development but was insufficient to improve leukemia control. In contrast, combined therapy with a cytotoxic agent and anti-PDL1 blockade eradicated measurable residual disease. This correlates with polarization of the neoantigen-specific CD4+ T-cell population from Tr1 toward T helper 1 (Th1) states. Our findings uncover a mechanism that enables leukemic relapse and resolves existing controversies on the role of immune surveillance toward this cancer type. Therapeutic polarization of neoantigen-specific CD4+ T cells away from Tr1 and toward Th1 states may improve contemporary immune therapies by reshaping the immune microenvironment toward states permissive for cytotoxic attack of residual leukemia.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024028194","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T19:22:06Z","timestamp":1757013726000},"page":"2779-2793","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":4,"title":["Leukemia escapes immunity by imposing a type 1 regulatory program on neoantigen-specific CD4+ T cells"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2938-3856","authenticated-orcid":false,"given":"Hrishi","family":"Venkatesh","sequence":"first","affiliation":[{"name":"1Center for Immunology, University of Minnesota, Minneapolis, MN"},{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9812-1200","authenticated-orcid":false,"given":"Enoc","family":"Granados Centeno","sequence":"additional","affiliation":[{"name":"1Center for Immunology, University of Minnesota, Minneapolis, MN"},{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9453-8279","authenticated-orcid":false,"given":"Qianyun","family":"Luo","sequence":"additional","affiliation":[{"name":"1Center for Immunology, University of Minnesota, Minneapolis, MN"},{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9085-9711","authenticated-orcid":false,"given":"Miriam","family":"Arroyo","sequence":"additional","affiliation":[{"name":"1Center for Immunology, University of Minnesota, Minneapolis, MN"},{"name":"3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2668-8005","authenticated-orcid":false,"given":"Lynn","family":"Heltemes-Harris","sequence":"additional","affiliation":[{"name":"1Center for Immunology, University of Minnesota, Minneapolis, MN"},{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8431-9964","authenticated-orcid":false,"given":"Todd P.","family":"Knutson","sequence":"additional","affiliation":[{"name":"4Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0584-0688","authenticated-orcid":false,"given":"Yinjie","family":"Qiu","sequence":"additional","affiliation":[{"name":"4Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7691-455X","authenticated-orcid":false,"given":"Allison","family":"Haaning","sequence":"additional","affiliation":[{"name":"4Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3950-8747","authenticated-orcid":false,"given":"Beau R.","family":"Webber","sequence":"additional","affiliation":[{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"5Center for Genome Engineering, University of Minnesota, Minneapolis, MN"},{"name":"6Stem Cell Institute, University of Minnesota, Minneapolis, MN"},{"name":"7Department of Pediatrics, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9325-432X","authenticated-orcid":false,"given":"Veronika","family":"Bachanova","sequence":"additional","affiliation":[{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"8Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5569-0366","authenticated-orcid":false,"given":"Michael A.","family":"Farrar","sequence":"additional","affiliation":[{"name":"1Center for Immunology, University of Minnesota, Minneapolis, MN"},{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"3Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7047-2589","authenticated-orcid":false,"given":"Sean I.","family":"Tracy","sequence":"additional","affiliation":[{"name":"1Center for Immunology, University of Minnesota, Minneapolis, MN"},{"name":"2Masonic Cancer Center, University of Minnesota, Minneapolis, MN"},{"name":"8Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"3","key":"2025120411215846800_bib1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/S1470-2045(12)70600-9","article-title":"Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial","volume":"14","author":"Vora","year":"2013","journal-title":"Lancet Oncol"},{"issue":"18","key":"2025120411215846800_bib2","doi-asserted-by":"crossref","first-page":"4153","DOI":"10.1182\/blood-2008-11-185132","article-title":"Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL)","volume":"113","author":"Bassan","year":"2009","journal-title":"Blood"},{"issue":"7","key":"2025120411215846800_bib3","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/s41375-018-0360-1","article-title":"Immune cell constitution in bone marrow microenvironment predicts outcome in adult ALL","volume":"33","author":"Hohtari","year":"2019","journal-title":"Leukemia"},{"issue":"10","key":"2025120411215846800_bib4","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1038\/s41375-020-0793-1","article-title":"Leukemia-induced dysfunctional TIM-3","volume":"34","author":"Blaeschke","year":"2020","journal-title":"Leukemia"},{"issue":"4","key":"2025120411215846800_bib5","first-page":"335","article-title":"Combining nilotinib and PD-L1 blockade reverses CD4+ T-cell dysfunction and prevents relapse in acute B-cell leukemia","volume":"140","author":"Tracy","year":"2022","journal-title":"Blood"},{"issue":"6","key":"2025120411215846800_bib6","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.immuni.2018.12.001","article-title":"The Biology of T regulatory type 1 cells and their therapeutic application in immune-mediated diseases","volume":"49","author":"Roncarolo","year":"2018","journal-title":"Immunity"},{"issue":"1","key":"2025120411215846800_bib7","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1002\/(SICI)1521-4141(199801)28:01<390::AID-IMMU390>3.0.CO;2-O","article-title":"Virus-specific MHC-class II-restricted TCR-transgenic mice: effects on humoral and cellular immune responses after viral infection","volume":"28","author":"Oxenius","year":"1998","journal-title":"Eur J Immunol"},{"issue":"4","key":"2025120411215846800_bib8","doi-asserted-by":"crossref","first-page":"2312","DOI":"10.4049\/jimmunol.0900185","article-title":"Nonredundant roles for B cell-derived IL-10 in immune counter-regulation","volume":"183","author":"Madan","year":"2009","journal-title":"J Immunol"},{"issue":"43","key":"2025120411215846800_bib9","doi-asserted-by":"crossref","first-page":"6166","DOI":"10.1038\/s41388-021-02012-z","article-title":"Identification of mutations that cooperate with defects in B cell transcription factors to initiate leukemia","volume":"40","author":"Heltemes-Harris","year":"2021","journal-title":"Oncogene"},{"issue":"8","key":"2025120411215846800_bib10","doi-asserted-by":"crossref","first-page":"4028","DOI":"10.4049\/jimmunol.1501291","article-title":"Adaptive immunity to leukemia is inhibited by cross-reactive induced regulatory T cells","volume":"195","author":"Manlove","year":"2015","journal-title":"J Immunol"},{"issue":"1","key":"2025120411215846800_bib11","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1038\/s41467-023-36180-1","article-title":"Germline T cell receptor exchange results in physiological T cell development and function","volume":"14","author":"Rollins","year":"2023","journal-title":"Nat Commun"},{"issue":"1","key":"2025120411215846800_bib12","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.immuni.2007.11.020","article-title":"A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation","volume":"28","author":"Matza","year":"2008","journal-title":"Immunity"},{"issue":"6","key":"2025120411215846800_bib13","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/nm.3179","article-title":"Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells","volume":"19","author":"Gagliani","year":"2013","journal-title":"Nat Med"},{"issue":"6","key":"2025120411215846800_bib14","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/s41590-021-00930-4","article-title":"Clonally expanded EOMES","volume":"22","author":"Bonnal","year":"2021","journal-title":"Nat Immunol"},{"issue":"7710","key":"2025120411215846800_bib15","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41586-018-0206-z","article-title":"Induction and transcriptional regulation of the co-inhibitory gene module in T cells","volume":"558","author":"Chihara","year":"2018","journal-title":"Nature"},{"key":"2025120411215846800_bib16","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.stem.2022.04.007","article-title":"Antigen presentation safeguards the integrity of the hematopoietic stem cell pool","volume":"29","author":"Hern\u00e1ndez-Malmierca","year":"2022","journal-title":"Cell Stem Cell"},{"issue":"8","key":"2025120411215846800_bib17","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1182\/blood-2009-06-230391","article-title":"Emergence of BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term imatinib mesylate treatment","volume":"115","author":"Riva","year":"2010","journal-title":"Blood"},{"issue":"5","key":"2025120411215846800_bib18","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1182\/blood-2016-07-731091","article-title":"BCR-ABL-specific T-cell therapy in Ph+ ALL patients on tyrosine-kinase inhibitors","volume":"129","author":"Comoli","year":"2017","journal-title":"Blood"},{"key":"2025120411215846800_bib19","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.coi.2019.04.014","article-title":"Heterogeneity and fate choice: T cell exhaustion in cancer and chronic infections","volume":"58","author":"Philip","year":"2019","journal-title":"Curr Opin Immunol"},{"issue":"2","key":"2025120411215846800_bib20","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.immuni.2016.07.011","article-title":"Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis","volume":"45","author":"Schietinger","year":"2016","journal-title":"Immunity"},{"issue":"1","key":"2025120411215846800_bib21","doi-asserted-by":"crossref","first-page":"68","DOI":"10.4049\/jimmunol.173.1.68","article-title":"T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1\/Th2 effector cells that provide help for B cells","volume":"173","author":"Chtanova","year":"2004","journal-title":"J Immunol"},{"key":"2025120411215846800_bib22","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1146\/annurev.immunol.26.021607.090344","article-title":"T follicular helper (TFH) cells in normal and dysregulated immune responses","volume":"26","author":"King","year":"2008","journal-title":"Annu Rev Immunol"},{"issue":"3","key":"2025120411215846800_bib23","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.immuni.2023.02.010","article-title":"Toward a general model of CD4 T cell subset specification and memory cell formation","volume":"56","author":"Osum","year":"2023","journal-title":"Immunity"},{"issue":"4","key":"2025120411215846800_bib24","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.immuni.2013.02.020","article-title":"Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection","volume":"38","author":"Hale","year":"2013","journal-title":"Immunity"},{"issue":"4","key":"2025120411215846800_bib25","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.immuni.2011.09.009","article-title":"Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells","volume":"35","author":"Pepper","year":"2011","journal-title":"Immunity"},{"issue":"1","key":"2025120411215846800_bib26","doi-asserted-by":"crossref","first-page":"7712","DOI":"10.1038\/s41467-023-43427-4","article-title":"Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states","volume":"14","author":"Podest\u00e0","year":"2023","journal-title":"Nat Commun"},{"issue":"6","key":"2025120411215846800_bib27","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1002\/eji.201041120","article-title":"Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells","volume":"41","author":"Magnani","year":"2011","journal-title":"Eur J Immunol"},{"issue":"617","key":"2025120411215846800_bib28","doi-asserted-by":"crossref","first-page":"eabf5264","DOI":"10.1126\/scitranslmed.abf5264","article-title":"Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients","volume":"13","author":"Chen","year":"2021","journal-title":"Sci Transl Med"},{"issue":"3","key":"2025120411215846800_bib29","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.4049\/jimmunol.1601045","article-title":"IL-10 receptor signaling is essential for TR1 cell function in vivo","volume":"198","author":"Brockmann","year":"2017","journal-title":"J Immunol"},{"key":"2025120411215846800_bib30","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.immuni.2020.04.014","article-title":"Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms","volume":"52","author":"Beltra","year":"2020","journal-title":"Immunity"},{"issue":"12","key":"2025120411215846800_bib31","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1182\/blood.2021013290","article-title":"Blinatumomab maintenance after allogeneic hematopoietic cell transplantation for B-lineage acute lymphoblastic leukemia","volume":"139","author":"Gaballa","year":"2022","journal-title":"Blood"},{"key":"2025120411215846800_bib32","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.clim.2018.02.009","article-title":"T cell exhaustion characterized by compromised MHC class I and II restricted cytotoxic activity associates with acute B lymphoblastic leukemia relapse after allogeneic hematopoietic stem cell transplantation","volume":"190","author":"Liu","year":"2018","journal-title":"Clin Immunol"},{"key":"2025120411215846800_bib33","doi-asserted-by":"crossref","first-page":"156371","DOI":"10.1016\/j.cyto.2023.156371","article-title":"A dual-role for IL-10: from leukemogenesis to the tumor progression in acute lymphoblastic leukemia","volume":"171","author":"Silva","year":"2023","journal-title":"Cytokine"},{"issue":"8023","key":"2025120411215846800_bib34","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/s41586-024-07752-y","article-title":"Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy","volume":"632","author":"Sultan","year":"2024","journal-title":"Nature"},{"issue":"10","key":"2025120411215846800_bib35","doi-asserted-by":"crossref","first-page":"e006619","DOI":"10.1136\/jitc-2022-006619","article-title":"PD-1 blockade in combination with dasatinib potentiates induction of anti-acute lymphocytic leukemia immunity","volume":"11","author":"Koller","year":"2023","journal-title":"J Immunother Cancer"},{"issue":"11","key":"2025120411215846800_bib36","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1016\/j.immuni.2021.08.020","article-title":"Antigen and checkpoint receptor engagement recalibrates T cell receptor signal strength","volume":"54","author":"Elliot","year":"2021","journal-title":"Immunity"},{"key":"2025120411215846800_bib37","doi-asserted-by":"crossref","first-page":"4741","DOI":"10.1038\/ncomms5741","article-title":"Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy","volume":"5","author":"Burton","year":"2014","journal-title":"Nat Commun"},{"issue":"6332","key":"2025120411215846800_bib38","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1126\/science.aaf1292","article-title":"T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition","volume":"355","author":"Hui","year":"2017","journal-title":"Science"},{"issue":"6332","key":"2025120411215846800_bib39","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1126\/science.aaf0683","article-title":"Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent","volume":"355","author":"Kamphorst","year":"2017","journal-title":"Science"},{"issue":"16","key":"2025120411215846800_bib40","doi-asserted-by":"crossref","first-page":"e2205085120","DOI":"10.1073\/pnas.2205085120","article-title":"Blockade of trans PD-L1 interaction with CD80 augments antitumor immunity","volume":"120","author":"Zhang","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"2025120411215846800_bib41","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1056\/NEJMoa1709919","article-title":"Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia","volume":"378","author":"Park","year":"2018","journal-title":"N Engl J Med"},{"issue":"9","key":"2025120411215846800_bib42","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1056\/NEJMoa1609783","article-title":"Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia","volume":"376","author":"Kantarjian","year":"2017","journal-title":"N Engl J Med"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/146\/23\/2779\/2469607\/blood_bld-2024-028194-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/146\/23\/2779\/2469607\/blood_bld-2024-028194-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T16:22:08Z","timestamp":1764865328000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/146\/23\/2779\/547099\/Leukemia-escapes-immunity-by-imposing-a-type-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,4]]},"references-count":42,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2025,12,4]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2024028194","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.12.21.629902","asserted-by":"object"}]},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12,4]]},"published":{"date-parts":[[2025,12,4]]}}}