Defining the impact of aging and obesity on T-cell ultrastructure and cancer immunosurveillance mechanisms 3959

Abstract Description The ultrastructure of T-cells dictates their functional capacity including extravasation, chemotaxis, cell-to-cell adhesion, immunological synapse formation, cytokine secretion, and cytolysis. We have recently discovered that adipocytes directly attenuate T-cell function by altering their ultrastructure (Kellner A, Hunter R, et al., bioRxiv, 2024). Analogous studies suggest that aging induces similar impairments in T-cell ultrastructure. These changes manifest as global reductions in actin/actin-binding protein levels, increased lipid deposition on the T-cell membrane, and attenuated biomechanical forces transmitted by the T-cell receptor with its target antigen. Thus, we hypothesize that immune cells and cancer cells in obese and aged microenvironments undergo significant biophysical changes that compromise cancer immunosurveillance mechanisms. To define how obesity and aging impact the ultrastructure of immune cells in non-malignant settings we examined mouse spleens using a custom spatial transcriptomics platform examining 479 genes. Further, we examined T-cells from human PBMCs donated by patients selected for age and BMI. Using flow cytometry, confocal microscopy, and other techniques we have identified shifts in T-cell function, and cytoskeletal integrity as a result of the obese and aged microenvironments. In summary, our studies provide novel mechanistic insight into how obesity and aging-induced ultrastructural changes impact the elimination of malignant cells. Funding Sources NCI 5T32CA190216-08 Training Program in Cancer Biology ACS 00112809 ACS 00112809 Institutional Funding: The Gates Foundation and SOM Dean Diversity Funding Topic Categories Immune Mechanisms of Human Disease (HUM)