GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE326nnn/GSE326061/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE326061GEOGSEfalseFc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote anti-tumor immunity [Lib1]Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that involves increased effector T cell activity and regulatory T cell (Treg) elimination. The pre-clinical anti-tumor activity of GITR mAbs depends on activating Fcγ receptors (FcγRs). However, the role of human Fc-FcγR interactions in the activity of GITR mAbs has not been comprehensively addressed. To this end, we employed Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized FcγR mice. We identified an Fc-optimized human IgG scaffold that increased binding to activating FcγRIIa and FcγRIIIa, enhancing anti-tumor efficacy. This Fc-optimized activity was mediated by multiple mechanisms that are unique to GITR mAb, including FcγR-mediated Treg depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to anti-tumor cytotoxic activity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.2026/05/12GSE326061GSM9621185GSM962118424247326061Mus musculus