Using CRISPR to enhance T cell effector function for therapeutic applications

Abstract

T cells are critical to fight pathogenic microbes and combat malignantly transformed cells in the fight against cancer. To exert their effector function, T cells produce effector molecules, such as the pro-inflammatory cytokines IFN-γ, TNF-α and IL-2. Tumors possess many inhibitory mechanisms that dampen T cell effector function, limiting the secretion of cytotoxic molecules. As a result, the control and elimination of tumors is impaired. Through recent advances in genomic editing, T cells can now be successfully modified via CRISPR/Cas9 technology. For instance, engaging (post-)transcriptional mechanisms to enhance T cell cytokine production, the retargeting of T cell antigen specificity or rendering T cells refractive to inhibitory receptor signaling can augment T cell effector function. Therefore, CRISPR/Cas9-mediated genome editing might provide novel strategies for cancer immunotherapy. Recently, the first-in-patient clinical trial was successfully performed with CRISPR/Cas9-modified human T cell therapy. In this review, a brief overview of currently available techniques is provided, and recent advances in T cell genomic engineering for the enhancement of T cell effector function for therapeutic purposes are discussed.

Keywords: AP-1, activator protein 1; ARE, AU-rich element; ARE-Del, deletion of the 3′UTR AREs from the Ifng/IFNG gene; CAR T cells; CAR, Chimeric Antigen Receptor; CRISPR; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeat; CRS, cytokine release syndrome; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; Cas, CRISPR-associated; Cas9; Cytokines; DGK, Diacylglycerol kinase; DHX37, DEAH-box helicase 37; EBV, Epstein Barr virus; FOXP3, Forkhead box P3; GATA, GATA binding protein; Genome editing; IFN, interferon; IL, interleukin; LAG-3, Lymphocyte Activating 3; NF-κB, nuclear factor of activated B cells; PD-1, Programmed cell Death 1; PD-L1, Programmed Death Ligand 1; PTPN2, Protein Tyrosine Phosphatase Non-Receptor 2; Pdia3, Protein Disulfide Isomerase Family A Member 3; RBP, RNA-binding protein; RNP, ribonuclear protein; T cell effector function; T cells; TCR, T cell receptor; TGF, transforming growth factor; TIL, Tumor Infiltrating Lymphocyte; TLRs, Toll-like receptors; TNF, tumor necrosis factor; TRAC, TCR-α chain; TRBC, TCR-β chain; UTR, untranslated region; tTCR, transgenic TCR.