Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors

Autor: Anne W. J. Martens, Inga Kavazović, Mia Krapić, Su Min Pack, Ramon Arens, Aldo Jongejan, Perry D. Moerland, Eric Eldering, Gerritje J. W. van der Windt, Felix M. Wensveen, Fleur S. Peters, Arnon P. Kater
Přispěvatelé: Clinical Haematology, AII - Cancer immunology, CCA - Cancer biology and immunology, Epidemiology and Data Science, AII - Inflammatory diseases, APH - Methodology, APH - Personalized Medicine, AII - Infectious diseases, Experimental Immunology
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Leukemia, 1-11. Nature Publishing Group
STARTPAGE=1;ENDPAGE=11;ISSN=0887-6924;TITLE=Leukemia
Leukemia, 37, 606-616. SPRINGERNATURE
Leukemia
Volume 37
ISSN: 0887-6924
1476-5551
DOI: 10.1038/s41375-023-01817-z
Popis: T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the expense of memory-precursor effector cells (MPEC). Stimulation of these T cells in vitro showed rapid induction of effector genes and suppression of key memory transcription factors only in presence of CLL cells, indicating epigenetic regulation. This was investigated in vivo by following antigen-specific responses of naive OT-I CD8(+) cells to mCMV-OVA in presence/absence of TCL1 B-cell leukemia. Presence of leukemia resulted in increased SLEC formation, with disturbed inflammatory cytokine production. Chromatin and transcriptome profiling revealed strong epigenetic modifications, leading to activation of an effector and silencing of a memory profile through presence of CLL cells. Secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in presence of CLL. Altogether, we show that presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.
Databáze: OpenAIRE
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