Gene-engineered human T cells targeting intrinsic checkpoint inhibitor CISH enhances anti-tumor immune response

Authors

• JH Kim
• DC Palmer
• N Restifo

Abstract

Cancer treatment has entered a new phase in personalized medicine with the advent of T cell based immunotherapy. Despite recent advances, universal therapies are impeded with many obstacles. Cancer cells continuously sculpt a challenging microenvironment to evade the host immune response and prevent T cell mediated tumor regression. Additionally, tumor interaction with T cells is capable of triggering inhibitory T cell-intrinsic molecules that suppress T cell activity. Previously, we demonstrated Suppressor of Cytokine Signaling (SOCS) family member Cish as a promising targetable molecule to improve inhibited anti-tumor T cells. Here, we genetically engineer primary human T cells with different viral and non-viral mediated strategies. The disruption of Cish using short hairpin microRNA’s was characterized by overall improved sensitivity to cognate antigens, functional avidity, and cytokine productivity in both in vitro co-culture and in vivo adoptive transfer experiments. Furthermore, we are attempting to genetically delete CISH in human T cells by using a lentiviral based Crispr/Cas9 technology. Genetic deletion of CISH using this new technology could result in significant increase of cytotoxicity, IFN- γ production, and IL-2 production, indicators of tumor-specific T cells properties. These findings establish Cish as a novel targetable inhibitory molecule demonstrating regulatory properties in tumor-specific CD8+ T cells, which can be manipulated to improve adoptive cancer immunotherapy.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021