{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:56:33Z","timestamp":1790679393835,"version":"4.1.0"},"reference-count":54,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HemaSphere"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Chronic lymphocytic leukemia (CLL) exhibits marked clinical heterogeneity that cannot be fully explained by genetic alterations, underscoring the critical role of the tumor microenvironment in disease progression and therapeutic resistance. To delineate the temporal evolution of immune dysregulation in CLL, we used the E\u00b5\u2010TCL1 adoptive transfer (TCL1\u2010AT) mouse model combined with high\u2010dimensional spectral flow cytometry to longitudinally profile lymphoid and myeloid compartments. To assess the reproducibility across different disease kinetics, we analyzed seven independent TCL1\u2010AT cohorts generated from distinct primary tumors. CLL progression was associated with coordinated restructuring of adaptive and innate immune cell populations. Within the T\u2010cell compartment, early activation and effector expansion transitioned to a progressive accumulation of terminally exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Concurrently, immunoregulatory populations expanded, including regulatory type 1 (Tr1)\u2010like CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, activated regulatory T cells (Tregs) and, importantly, a previously underappreciated Eomes\u2010expressing Treg subset. Natural killer (NK) cells exhibited transient expansion followed by differentiation and acquisition of exhaustion markers. Myeloid cell profiling revealed an expansion of immunosuppressive PD\u2010L1\n                    <jats:sup>high<\/jats:sup>\n                    patrolling monocytes, mature regulatory dendritic cells (mregDCs), and phenotypic reprogramming of dendritic cells (DCs) consistent with impaired antigen presentation and promotion of T\u2010cell exhaustion and regulatory T\u2010cell subsets. Despite substantial variation in leukemia kinetics, expansion of patrolling monocytes, exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and Tregs was consistently observed across all seven independent TCL1\u2010AT cohorts, demonstrating robust immune remodeling. Collectively, our findings demonstrate a stepwise transition toward a suppressive microenvironment involving innate and adaptive immune compartments in the E\u00b5\u2010TCL1 mouse model, providing a framework for understanding immune failure in CLL and informing strategies to restore anti\u2010leukemic immunity.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70476","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T15:45:10Z","timestamp":1789400710000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["High\u2010dimensional spectral flow cytometry uncovers progressive T\u2010cell exhaustion and myeloid cell reprogramming in a CLL mouse model"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-1262-5219","authenticated-orcid":false,"given":"Hannah","family":"Briesch","sequence":"first","affiliation":[{"name":"Immune Modulation in Cancer German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Division of Molecular Genetics German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Faculty of Biosciences Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6010-1220","authenticated-orcid":false,"given":"Mariana","family":"Coelho","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Faculty of Biosciences Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Floerchinger","sequence":"additional","affiliation":[{"name":"Immune Modulation in Cancer German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Division of Molecular Genetics German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Faculty of Biosciences Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9317-4709","authenticated-orcid":false,"given":"Yuliia","family":"Borysovych","sequence":"additional","affiliation":[{"name":"Immune Modulation in Cancer German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Division of Molecular Genetics German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Faculty of Biosciences Heidelberg University Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4222-6764","authenticated-orcid":false,"given":"Nicolas","family":"Aubert","sequence":"additional","affiliation":[{"name":"Immune Modulation in Cancer German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Division of Molecular Genetics German Cancer Research Center (DKFZ) Heidelberg 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