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

T-cell dysregulation in chronic lymphocytic leukaemia (CLL) associates with low response rates to autologous T-cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. The authors investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in the presence of CLL in vitro and 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 the presence of CLL cells, indicating epigenetic regulation. A secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in the presence of CLL. Altogether, the study demonstrated that the presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.