Session: 641. Chronic Lymphocytic Leukemia: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Fundamental Science, Research, Immunology, Metabolism, Biological Processes
Splenocytes from transgenic Eμ-TCL1 mice were adoptively transferred (AT) into wild-type syngeneic C57BL/6 mice. Splenic T cells were evaluated for alterations in the expression of ER unfolded protein response (UPR) targets at the protein and gene levels. Moreover, T cells' metabolic and differentiation trajectory changes were assessed on the transcriptional and epigenetic levels at various disease stages. Ddit3T cell-KO mice were AT with leukemic Eμ-TCL1 splenocytes and were monitored for peripheral leukemic burden and survival.
Eμ-TCL1 T cells showed significant upregulation of UPR targets, including PERK, phospho-PERK, XBP1s, and the downstream target CHOP. Moreover, there were substantial changes in T-cell ER mass measured by the ER tracker green probe at different disease stages. The ER stress response disturbance was associated with depolarized dysfunctional mitochondria accumulation, elevated reactive oxygen species (ROS) levels, and reduced spare respiratory capacity post-T-cell receptor (TCR) activation. Moreover, these metabolic changes were associated with terminal differentiation and an exhausted-like T-cell phenotype characterized by a significant increase in TOX, Eomes, and PD-1 and a marked reduction in the self-renewal factor TCF-1. AT of Eμ-TCL1 splenocytes into Ddit3T cell-KO mice showed slower disease progression and improved survival compared to control mice.
Our research has uncovered for the first time the upregulation of the ER stress response activity in CLL T cells that goes hand in hand with mitochondrial disturbance and T-cell exhaustion. Additionally, we highlight the specific role of CHOP in T cells in controlling CLL progression in the murine model. These findings will enable us to identify novel targets that can be investigated for rejuvenating CLL T-cell activity to enhance the efficacy and persistence of ACT products for CLL.
Disclosures: Chavez: Abbvie: Consultancy; GenMab: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Novartis: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Lilly: Honoraria, Speakers Bureau; Janssen: Honoraria; ADC Therapeutics: Consultancy; Cellectis: Consultancy; Allogene: Consultancy; AstraZeneca: Consultancy; Merck: Research Funding. Pinilla-Ibarz: Takeda: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pfizer: Consultancy; Eli Lily: Consultancy, Speakers Bureau; Secura Bio: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Novartis: Honoraria; AbbVie: Consultancy, Speakers Bureau; Bristol Meyers Squibb: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.
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