CHRONIC LYMPHOCYTIC LEUKEMIA INDUCES SKEWING OF (ANTIGEN-SPECIFIC) T CELL RESPONSES TOWARDS A DYSFUNCTIONAL SHORT-LIVED EFFECTOR PHENOTYPE
Author(s): ,
Anne Martens
Affiliations:
Experimental Immunology,Amsterdam UMC,Amsterdam,Netherlands;Department of Hematology,Amsterdam UMC,Amsterdam,Netherlands
,
Jaco van Bruggen
Affiliations:
Experimental Immunology,Amsterdam UMC,Amsterdam,Netherlands;Department of Hematology,Amsterdam UMC,Amsterdam,Netherlands
,
Felix Wensveen
Affiliations:
Department of Histology and Embryology,University of Rijeka,Rijeka,Croatia
,
Ramon Arens
Affiliations:
Department of Immunohematology and Blood Transfusion,Leiden University Medical Center,Leiden,Netherlands
,
Eric Eldering
Affiliations:
Experimental Immunology,Amsterdam UMC,Amsterdam,Netherlands
,
Gerritje van der Windt
Affiliations:
Experimental Immunology,Amsterdam UMC,Amsterdam,Netherlands;Department of Hematology,Amsterdam UMC,Amsterdam,Netherlands
Arnon Kater
Affiliations:
Department of Hematology,Amsterdam UMC,Amsterdam,Netherlands
EHA Library. Martens A. Jun 14, 2019; 266156; PF356
Anne Martens
Anne Martens
Contributions
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Abstract

Abstract: PF356

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

Background
In recent years, CAR T cells showed to be highly effective in B cell malignancies such as acute lymphocytic leukemia. However, for chronic lymphocytic leukemia (CLL) efficacy of autologous T cell therapies is rather limited. T cells of CLL patients have a dysfunctional, terminally differentiated phenotype, which might be linked with the lack of success of T cell therapies. Recently it was shown that presence of memory T cell subsets in the CAR T cell infusion product associated with complete responses in CLL (Fraietta et al., 2018). 

Aims
It remains to be elucidated how CLL cells influence T cell skewing and whether this affects T cell responses in vivo. In this context, we functionally investigated acute T cell responses in the TCL1 mouse model, which features similar T cell dysfunction as observed in CLL patients (Gorgun et al., 2009). We applied a set-up that allows to study the response against acute infection of (1) endogenous CD8+ T cells, which have been exposed to leukemic cells during CLL development, and (2) the antigen-specific response of naïve, transferred OT-I T cells.

Methods
C57BL/6J (CD45.2+) mice were injected i.p. with 20x106 TCL1 splenocytes or PBS. When CD5+ leukemia reached 70% cells in blood, 50.000 naïve ovalbumin-specific CD8+ T cells (OT-I, CD45.1+) were injected i.v. Next, all mice were infected with mCMV-OVA and sacrificed 7 days later. Splenocytes were analyzed directly or after in vitro ovalbumin stimulation by FACS. 

Results
(1) Already prior to infection, we found a skewing towards antigen-experienced cells in the endogenous CD8+ compartment of leukemic mice. After mCMV-OVA infection, a population of naïve CD8+ T cells persisted in control mice,  but in leukemic mice the complete CD8+ compartment differentiated into effector cells. Within the effector compartment, we found a skewing to the short-lived effector cell (SLEC) phenotype in the leukemic mice, while memory precursor effector cells (MPEC) were reduced. This skewing towards SLEC associated with increased effector-associated T-bet expression. 

 (2) Analysis of the OT-I cells allowed to perform detailed study of the impact of leukemia on an antigen-specific response. Seven days after infection, spleens of leukemic and control mice contained similar frequencies of differentiated OT-I cells, that had an effector phenotype. Also here, TCL1-derived OT-I cells showed a decreased percentage of MPEC, while SLECs were increased (Figure 1), indicating impaired memory formation. In correlation with skewing towards SLECs in leukemic mice, these OT-I cells showed reduced expression of memory-associated transcription factor Bcl6, while T-bet was also increased. Earlier it was shown that Bcl6 is able to repress glycolysis, essential for T cell effector function (Oestreich et al., 2014). In line with reduced Bcl6 expression, we found increased glucose uptake in TCL1-derived OT-I cells. Despite the skewing towards SLEC phenotype, the TCL1-derived OT-I cells showed decreased production of IFNγ and TNFα and decreased degranulation (CD107a expression) upon in vitro restimulation.

Conclusion
In this murine model of CLL, both bystander T cells as well as acute antigen-specific T cell responses are driven towards an SLEC phenotype with signs of functional impairment, and metabolic alterations. This approach may provide crucial insight into the interplay between CLL and T cells, and the underlying failure of cancer immune surveillance.  

Session topic: 5. Chronic lymphocytic leukemia and related disorders - Biology & Translational Research

Keyword(s): Antigen-specific T cells, Cancer immunotherapy, Chronic lymphocytic leukemia, T cell response

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