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Abstract
Cancer immunotherapies provide benefit to patients with different tumour types, but are hampered by low response rates and resistance, demanding novel therapeutics. A potential link was identified between WD40 repeat domain (WDR) proteins, a family of scaffolding proteins with druggable structures, and T cell activation. Using gene-silencing technologies, their roles in T cell activation were studied. I hypothesized that loss of WDR proteins which are negative regulators will increase Jurkat T cell activation. CRISPR knockout (KO) of RBBP4 or RBBP7 enhanced CD69 expression levels. While silencing of the paralogs RBBP4/7 differentially affected IL2 secretion, they also differentially affected proliferation. Greater toxicity was observed with loss of RBBP4 vs. RBBP7, implying different cellular roles. Immune-protective gene pathways were upregulated after RBBP7 KO, like the known negative regulator Cbl-b. These results support a negative regulatory role for RBBP7 in T cell activation, paving the way to broadening therapeutic targets for cancer immunotherapy.