Investigating the effect of second generation immune checkpoint inhibitors on intrahepatic Tregs 4288

Abstract Description Introduction Regulatory T cells (Tregs) are an immunosuppressive and pro-tumor subset of CD4+ T cells that inhibit effective responses to immune checkpoint inhibitors (ICIs). Tregs exert their immunosuppressive function through multiple mechanisms, including IL10 expression and surface expression of T cell exhaustion markers. Although second-generation checkpoint inhibitors are FDA-approved, the effects of inhibiting these mechanisms on intrahepatic Tregs has not been previously studied. Methods Publicly-available scRNA-seq data from purified murine Tregs were re-analyzed. Anti-IL-10, anti-PD-1, anti-LAG-3, or anti-TIM3 were administered IP x1 to C57B6 mice. Liver and spleen NPCs were collected and analyzed via flow cytometry after 72 hours. Results Hepatic effector Tregs expressed high Pdcd1, Havcr2, Lag3, and Il10 mRNA. Anti-PD1 induced expansion of a CD29+ Treg subpopulation. Anti-Lag3, anti-Tim3, and IL-10 neutralization did not appear to expand, maintain, or recruit Tregs. Conclusion Second generation ICIs anti-LAG3 and anti-TIM3 have the potential to be utilized as a combination therapy for HCC patients due to their inability to elevate the quantity, proliferation, and suppressive capacity of immunosuppressive hepatic Tregs. Funding Sources Supported by National Cancer Institute, National Institutes of Health, United States (R01CA222490, R50CA243787, and T32 CA108459-15); IDeA Networks of Biomedical Research Excellence (INBRE) Award number: P20GM103466; Ola Hawai’i Pilot Project (NIMHD #2U54MD007601-36); Andrew And Mary Weinberg Foundation. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)