Peptide-mediated modulation of complement-like CD109 boosts T cell anti-tumor responses 2967

Description Immune cell autonomous complement expression and function emerges as pivotal regulator of tissue immunity and T cell biology. Specifically, CD4 T cell intrinsic engagement of CD46 during T cell stimulation is required for normal Th1 response. We identified CD109, a GPI anchored C3 complement-like protein amongst the top up-regulated CD46 signaling targets. A direct function for CD109 on T cells has not been described. We found that human CD4+ T cells lacking CD109 displayed significantly augmented IFN-g and IL-17 production upon in vitro stimulation. Similarly, CD4+ T cells from Cd109–/– mice showed in vitro Th1 and Th17 hyperactivation and caused increased EAE pathology in vivo. Unexpectedly, T cell CD109 fails to control TGF-b signaling but rather restrains IFN-g and/or IL-17 production by binding to and inhibiting the activity of a non-canonical costimulator linked to Th1/Th17 biology. Guided by modeling and atomic force microscopy data, we designed a CD109/costimulator inhibitory peptide, which fully recapitulated the phenotype observed in CD109-deficient T cells. Furthermore, inhibiting CD109’s restraint on cytokine release using this peptide boosted CAR T cell tumor-killing capacity in vitro. Together, these data suggest that CD109 is an unexpected and important brake on CD4 T cell co-stimulatory signals upstream of Th1/Th17 inflammatory pathways, and that modulating its function pharmacologically can be leveraged to improve CAR T cell responses against tumors. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)