Session: 703. Cellular Immunotherapies: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, immune mechanism, immunology, metabolism, Biological Processes
Our lab previously observed that treatment of mice with the mammalian cyclic dinucleotide (CDN) 2’3’-cGAMP increased the persistence and proliferation of Th/Tc17 cells expressing an anti-neu CAR in a model of locally advanced breast cancer. CDNs are evolutionarily conserved second messengers that classically activate the innate immune system in response to pathogens by binding to pattern recognition receptors, but more recent data shows that they are also important in the antitumor immune response by modulating tumor immunogenicity. We now extend those findings and show that treatment of isolated T cells with cGAMP induces a T cell intrinsic mechanism that drives Tscm formation in ex vivo expanded murine T cells. Th/Tc17 cells treated with cGAMP during their in vitro differentiation and expansion show a 5-10 fold increase in Tscm compared to control cells. This is supported by increased expression of the transcription factors Tcf7 and Lef1, which are key mediators in maintaining T cell stemness and memory.
Though CDNs are thought to mediate their downstream effects mainly through activation of the adaptor protein STING (stimulator of interferon genes), our data indicates that CDNs promote T cell memory independent of canonical STING activation in Th/Tc17 cells. This may in part explain why we see minimal cytotoxicity in Th/Tc17 cells treated with cGAMP as compared to prior reports which observed STING dependent cell death following CDN exposure in other T cell subsets. Instead, CDNs activate AMPK (AMP-activated protein kinase) leading to metabolic reprogramming in Th/Tc17 cells. Total RNA sequencing data and functional studies of cellular bioenergetics point to reduced glycolytic metabolism following cGAMP treatment. Downstream of AMPK activation we also observe inhibition of acetyl-CoA carboxylase (ACC), the rate limiting enzyme in fatty acid synthesis, and upregulation of Cpt1a which is key to FAO, suggestive of enhanced fatty acid usage as a fuel source. Collectively this metabolic profile favors the production of Tscm and further work is ongoing to delineate the molecular mechanisms behind this cGAMP triggered metabolic switch. As there is increasing evidence that tumor cells secrete 2’3’-cGAMP in the TME, this pathway could be readily targeted to manipulate the bioenergetics of CAR T cells to maximize their memory potential and enhance their in vivo persistence and function.
Disclosures: Serody: STING activation: Patents & Royalties: provisional patent to enhance CAR therapy for solid tumors/ provisional patent for the use of ILC2 cells to treat or prevent GvHD.
See more of: Oral and Poster Abstracts