Session Time: 3:15pm-4:45pm
Presentation Time: 4:03pm-4:15pm
*Purpose: Donor-specific regulatory T-cell (Treg) therapy has emerged as a potent strategy to promote immune tolerance in experimental transplantation. However, a major stumbling block in the clinical use of donor-specific Tregs is their very limited number. Recently, the potential of chimeric antigen receptor (CAR) technology was investigated to redirect antigen-specificity of Tregs toward a relevant alloantigen. However, whether or not the type of CAR costimulatory domain (CSD) impacts the stability, persistence and function of CAR Tregs remains largely unexplored.
*Methods: Here, we used HLA-A2-targeted CAR Tregs incorporating either 4-1BB or CD28 CSD to study their effect on Treg biology and to assess their therapeutic potential in transplantation settings.
*Results: CAR Tregs elicited HLA-A2-specific suppression both in vitro and in vivo in a humanized mouse model where xenogeneic graft versus host disease (xeno-GVHD) was induced by the adoptive transfer of HLA-A2+ peripheral blood mononuclear cells. We found that the type of CSD significantly influenced the proliferative capacity and immunometabolism of CAR-Tregs, with ensuing effect on their stability (Foxp3 and Helios expression). Moreover, CAR-Treg activation and differentiation also greatly varied across CSD: 1- 41BB CSD steered CAR-Tregs toward effector differentiation. 2- Although activation through the CAR was not different between the two CSD at early time points in the culture, the type of CSD dramatically determined subsequent occurrence of CAR-Treg hyporesponsiveness to antigen stimulation. In vivo bioluminescent tracking of HLA-A2-targeted CAR Tregs demonstrated different homing capacities into lymphoid organs and sustainity according to CSD. Finally, both HLA-A2-targeted CAR Tregs were able to prevent xeno-GVHD, yet with different long-term efficacies.
*Conclusions: Together, our data provide new insights to optimize human CAR-Tregs engineering on the path toward clinical development.
To cite this abstract in AMA style:Lamarthée B, Marchal A, Charbonnier S, Blein T, Vogt K, Titeux M, Pallet N, Delville M, Six E, Anglicheau D, Legendre C, Sawitzki B, Taupin J, Cavazzana M, André I, Zuber J. Costimulatory Signal Impacts Car Treg Fate and Function in Transplantation [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/costimulatory-signal-impacts-car-treg-fate-and-function-in-transplantation/. Accessed March 4, 2021.
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