You Are What You Eat:� The Impact of Obesity on B-ALL Pathogenesis and Therapeutic Responses

Relapsed B-cell acute lymphoblastic leukemia (B-ALL) is the second leading cause of childhood cancer with survival outcomes declining by 30% in obese relative to lean pediatric patients receiving chemotherapy treatment. Poor survival outcomes in obese pediatric patients with B-ALL has largely been attributed to altered chemotherapy pharmacokinetics; whereas, the direct impact of the obese microenvironment on B-ALL cells and T-cell immunity has been largely unexplored. We have found that adipocytes directly induce chemoresistance in murine and human B-ALL cells. Furthermore, we have observed compromised T-cell function in murine models of obesity and in obese patients with B-ALL. Mechanistically, we found that adipocytes induce Galectin-9 (GAL-9) surface expression on B-ALL cells which promotes chemoresistance and attenuates T-cell mediated immunity. We have discovered that antibody-mediated blockade of GAL-9 promotes extensive cell death in adipocyte-conditioned B-ALL cells in vitro and significantly prolongs the survival of obese mice transplanted with B-ALL cells relative to those receiving chemotherapy treatment. Results from these studies highlight a novel approach to overcome obesity-induced chemoresistance and serve as the foundation for engineering chimeric antigen receptor (CAR) T-cells expressing anti-GAL-9 antibodies to improve survival outcomes in obese patients with B-ALL.