{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T06:23:42Z","timestamp":1787207022017,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"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":"\n Background<\/jats:title>\n Blinatumomab (Blina), a CD19\u00d7CD3 bispecific T cell engager, is approved for the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), yet resistance remains a major challenge and the mechanisms driving treatment failure remain poorly understood.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n To define the immunological determinants of resistance, we performed longitudinal profiling of peripheral blood T cells and the immune milieu of 34 patients receiving Blina using flow cytometry (n=19), single-cell CITE-seq (n=13),\n ex vivo<\/jats:italic>\n Blina-induced cytotoxicity (n=26) and serum proteomics (n=17).\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n At baseline, Responders (R) were enriched for CD8\n +<\/jats:sub>\n effector memory T cells (T\n EM<\/jats:sub>\n ) expressing higher levels of cytotoxic genes and their transcriptional regulator\n ZNF683<\/jats:italic>\n . Conversely, CD8\n +<\/jats:sup>\n T\n EM<\/jats:sub>\n from Non-Responders (NR) displayed transcriptional features of activation without proportionate cytotoxic commitment. Over the course of the first treatment cycle, NR exhibited a progressive expansion of TIM3\n +<\/jats:sub>\n CD8\n +<\/jats:sub>\n T cells that correlated with a rapid loss of\n ex vivo<\/jats:italic>\n cytotoxic function. Linking baseline state to post-treatment T-cell exhaustion, the magnitude of TIM3\n +<\/jats:sub>\n CD8\n +<\/jats:sub>\n expansion correlated inversely with baseline\n ZNF683<\/jats:italic>\n expression in CD8\n +<\/jats:sub>\n T\n EM<\/jats:sub>\n . Beyond T-cell-intrinsic features, NR harbored an immunosuppressive milieu characterized by higher circulating levels of M2-polarizing factors (CSF-1, HGF) and the TIM-3 ligand Galectin-9, which correlated positively with the magnitude of TIM3\n +<\/jats:sub>\n CD8\n +<\/jats:sub>\n T-cell expansion.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n These findings indicate that post-Blina CD8\n +<\/jats:sup>\n T-cell exhaustion is associated with resistance and it is shaped by both reduced\n ZNF683<\/jats:italic>\n -dependent cytotoxic programming in CD8\n +<\/jats:sub>\n T\n EM<\/jats:sub>\n and an immunosuppressive milieu. This provides a rationale for risk stratification based on baseline transcriptional profiling of CD8\n +<\/jats:sub>\n T\n EM<\/jats:sub>\n and for combinatorial strategies targeting the suppressive microenvironment.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1895742","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:27:54Z","timestamp":1787203674000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pre-treatment T cell features and immune-milieu characteristics shape treatment-induced exhaustion and resistance to Blinatumomab in B-cell acute lymphoblastic leukemia"],"prefix":"10.3389","volume":"17","author":[{"given":"Francesco","family":"Corrado","sequence":"first","affiliation":[{"name":"Laboratory for Translational Cancer Immunology, LMU Gene Center","place":["Munich, 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III, LMU University Hospital, Ludwig Maximilian University (LMU) Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Nixdorf","sequence":"additional","affiliation":[{"name":"Laboratory for Translational Cancer Immunology, LMU Gene Center","place":["Munich, Germany"]},{"name":"Department of Medicine III, LMU University Hospital, Ludwig Maximilian University (LMU) Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelie","family":"Muth","sequence":"additional","affiliation":[{"name":"Laboratory for Translational Cancer Immunology, LMU Gene Center","place":["Munich, Germany"]},{"name":"Department of Medicine III, LMU University Hospital, Ludwig Maximilian University (LMU) Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Rappa","sequence":"additional","affiliation":[{"name":"Laboratory for Translational Cancer Immunology, LMU Gene Center","place":["Munich, Germany"]},{"name":"Department of Medicine III, LMU University Hospital, Ludwig Maximilian University (LMU) Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnese","family":"Petrera","sequence":"additional","affiliation":[{"name":"Metabolomics and Proteomics Core Facility, Helmholtz Center Munich - German Research Center for Environmental Health (GmbH)","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Scheurer","sequence":"additional","affiliation":[{"name":"Department of Medicine III, LMU University Hospital, Ludwig Maximilian University (LMU) Munich","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Feng","family":"Chu","sequence":"additional","affiliation":[{"name":"TranslaTUM at Technical University of Munich","place":["Munich, Germany"]},{"name":"Department of 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