Singapore Initiative in Next Generation T-cell Decoding for Immunotherapy (SiT-Decode)

Our goal is to generate paradigm-shifting fundamental Next Generation understanding of the role of every annotated human gene in the regulation of T-cell functioning, and develop novel anticancer immunotherapeutic T-cell targets, focusing on hepatocellular carcinoma (HCC) and lymphoma. Current understanding of the role of every annotated human gene in regulating these functions of T-cells is minimal, severely limiting knowledge on both the mechanisms regulating T-cell functioning and novel drug targets for T-cell immunotherapy. Our study will eliminate this critical knowledge bottleneck in T-cell field, by interrogating the hypothesis that identification of previously unrecognized T-cell regulatory genes will reveal powerful novel T-cell immunotherapeutic targets. We will discover novel genes regulating T-cell functioning through genome-wide functional reverse genetic screening in human/mouse T-cells using cutting edge CRISPR-technology, wherein we will ablate the expression all 18000 protein coding genes individually to assess their role in T-cell activities. After discovering key novel genes/signaling modules regulating T-cells, we will characterize novel T-cell regulation mechanisms, and develop selected new genes as novel druggable T-cell immunotherapeutic targets using a solid tumour, hepatocellular carcinoma (HCC) and lymphoma as model systems, using in vitro and in vivo preclinical models. We will also evaluate existing drugs targeting our novel targets for their therapeutic efficacy against HCC and lymphoma in model systems. In addition, we will develop partnerships with Singapore-based drug discovery leaders and initiate the discovery of new therapeutic drugs (e.g., antibody) targeting our newly-discovered immunotherapeutic T-cell targets. This study will identify novel immunotherapy targets, and will expand immunotherapeutic intellectual property space. The proposed research programme will be accomplished through four individual interlinked projects: Project-1: T-cell activation and Immune Checkpoint Regulator Gene Discovery. Project-2: CD8+ T-cell Cytotoxic Effector Function Regulator Gene Discovery. Project-3: Treg Suppressor Function Regulator Gene Discovery. Project-4: Pre-clinical evaluation of novel targets for cancer immunotherapy.