Keynote Presentation: Delineating the Pleiotropic Impact of Obesity on T-cell Function and Immunotherapy Efficacy with Live Q&A

The obesity pandemic is concerning for a multitude of reasons, one of which is the association between increased adiposity, cancer incidence, and higher mortality rates observed in patients who fall within this demographic. The obesity-induced drivers of various subtypes of cancers are under investigation with our group and others attempting to delineate how adipocyte-induced alterations in the immune landscape impact cancer progression and therapeutic responses.

By studying how obesity impacts B-cell acute lymphoblastic leukemia (B-ALL) development, we have found that adipocytes directly decreased chemosensitivity and compromise anti-leukemia immunity. Regarding the latter, we have found that adipocyte-mediated immunosuppression reduces the function of T-cells and myeloid cells, with the former showing compromise proliferative responses, reductions in the production of pro-inflammatory cytokines, and attenuated cytolytic capabilities. Adipocyte-mediated T-cell defects resulted from reductions in genes coding for T-cell signaling machinery and alterations in the ultrastructure of T-cells, which significantly reduced the biomechanical properties of T-cells when they encountered B-ALL cells. Notably, these defects could not be overcome in the presence of the immunotherapy blinatumomab, where human T-cells failed to kill a large percentage of human B-ALL cells in co-culture assays.

Overall, our work demonstrates that adiposity promotes B-ALL development by compromising the function of endogenous T-cells, which reduces the efficacy of T-cell licensing immunotherapies targeting blood cancers.

Learning Objectives:

1. Explain how obesity impacts the survival of pediatric patients with specific subtypes of leukemia.

2. Describe how obesity impacts T-cell function in pediatric populations with and without leukemia.

3.Discuss how adiposity impacts the efficacy of T-cell based immunotherapies targeted at B-cell malignancies.