Keeping T Cells Young and Fabulous: Modulating Metabolic and Developmental Pathways to Promote a Memory Phenotype

BSC-Ursa Minor 115

T cell immunological efficacy is rooted in the ability to sustain a memory response to pathogens. Upon antigen encounter, naïve T cells differentiate into stem cell memory T cells (T_SCM) and central memory T cells (T_CM) which exhibit self-renewal capabilities to enable a long-lasting memory response . In adoptive T cell therapies, one of the challenges to effectively combating cancers involves limitations surrounding methods for ex vivo T cell expansion which favor memory phenotypes (Priceman et al., 2015). Considering this it is important to explore potential pharmacological means of promoting T cell stemness. Here, we evaluated modulators of 4 different pathways in order to ascertain whether inhibition or agonization of different pathways enhances T cell stemness. By in vitro phenotyping T cells via flow cytometry, we assessed which agonists and antagonists affected stem-like marker presentation on the surface of T cells over the course of 28 days while considering expansion and overall viability. Agonistic modulation of pathway 1 exhibited potential for memory phenotype promotion. Agonists of pathway 2 did not hinder growth at our working concentrations while antagonists accelerated exhaustion. Modulator X accelerated differentiation and modulator Y did not affect phenotype at our working concentrations. These pathways function in T cell differentiation and can be manipulated in vitro to maintain a T_SCM/T_CM phenotype.