Assessing the role of FcγRIIIa expression on CD8 T cells
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE279890 | GEO | 2025/06/17
REPOSITORIES: GEO
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Project description: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.
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Project description:Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells (Treg). The pre-clinical anti-tumor activity of GITR mAbs depends on activating Fcγ receptors (FcγRs). However, the human Fc-FcgR interactions in the activity of GITR mAbs have not been comprehensively investigated. 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 FcgR mice. We identified an Fc-optimized human IgG scaffold that enhances anti-tumor efficacy through multiple FcgR-mediated mechanisms, including Treg depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to anti-tumor cytotoxicity 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.
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Project description:Assessing the role of FcγRIIIa expression on CD8 T cells
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