DUSP2 functions as a negative regulator of cytotoxic T cell responses in cancer immunotherapy

Abstract Only a small cohort of patients show durable responses to immune checkpoint inhibitor (ICI) therapy and the mechanisms regulating CD8 T cell ICIs are yet be elucidated. To that end, we explored intrinsic factors may attributed low ICI response rates. We have identified Dual Specificity Phosphatase 2 (DUSP2) as potential negative regulator within cells. demonstrated DUSP2 expression in human cells is transient, peaking at two-hours post-T stimulation with rapid waning thereafter. Downregulation DUSP2, via siRNA transfection, increased cytotoxicity activated for 48-hours prior inclusion four-hour tumor killing co-culture assay, despite return baseline levels this time-point. Additionally, overexpression, mRNA decreased release effector molecules (Granzyme B Interferon-gamma) from 24-hours post-activation when compared control mRNA. When utilized RNA-sequencing analyze compare differentially expressed genes between responders non-responders therapy, found CX3CR1 positive consistently but not non-responders. Since identify highly resilient cytotoxic subset hypothesize negatively regulates ICI-responsive Thus, uncovering role provide target improve efficacy limited therapeutic alternatives. Mayo Clinic Department Immunology Pilot Award Center Individualized Medicine