Obese microenvironments attenuate the efficacy of endogenous and CD19-directed CAR T-cells

Abstract

Abstract Background: Hematological malignancies represent the largest class of cancers in pediatric patients. Despite successes in treating primary diseases, patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) and diffuse large B-cell lymphoma (DLBCL) have significantly lower survival outcomes. This has led to the use of immunotherapies, notably chimeric antigen receptor (CAR) T-cells, to treat relapse. Unfortunately, only 50% respond to CAR-T therapy, with relapse common in less than a year. Objective: Given that obesity is associated with poorer survival outcomes in pediatric patients with B-cell malignancies and promotes a loss of immune homeostasis, we hypothesize that obesity compromises the function of endogenous and engineered T-cells in B-cell malignancies. Results: Using in vitro models of adiposity and diet-induced obesity mouse models to study the impact of obesity on primary T-cell function, we observe defects in proliferation, cytokine production, and the upregulation of cytolytic mediators when cultured in adipocyte but not in bone marrow cell or unconditioned media. The introduction of CD19-direct CARs did not overcome adipocyte-induced defects in T-cell function, which resulted in increased PD-1 surface expression, compromised cytokine production, and defective killing of human CD19-expressing B-ALL cells. Interestingly, human B-ALL cells cultured in adipocyte-secreted factors downregulated CD19, suggesting that adipocytes promote B-ALL pathogenesis by compromising T-cell function and reducing the surface expression of antigens on target cells. Conclusion: Our studies are the first to demonstrate the inhibitory impact of the adipocyte secretome on CAR T-cell function in models of B-ALL.