Docking protein-1 in macrophage immunotherapy of gastric cancer

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Gastric cancer (GC) patients usually present at an advanced stage, where effective treatment is impossible, resulting in poor clinical outcome. Although the incidence and prevalence of GC in China and world-wide is declining, the mortality from GC in an ageing population is still high and a challenging health problem. Novel therapies were designed to boost the host immune response towards a tumor-attacking mode, preventing immune evasion and host anergy. However, the underlying mechanisms that warrant clinical efficacy of immunotherapies, e.g. such as antibodies against immune checkpoints (PD1/PD-L1), in GC are unknown. Docking protein-1 (DOK1) is an intracellular adapter which inhibits oncogenic Ras signaling and controls immune receptor activities. DOK1 is induced by insulin sensitizers (glitazones) and stabilized by interaction with peroxisome proliferator-activated receptor-gamma (PPARg), resulting in attenuated GC growth in vitro and in vivo. We have recently shown that DOK1 inhibits PD-L1 expression and promotes polarization and effector functions of human macrophages towards the tumor-attacking, pro-inflammatory M1 phenotype. Alterations in DOK1 and M1 (e.g. toll-like receptors) genes conferred poor prognosis in GC patients, and DOK1 mRNA/protein was differentially regulated during tumor progression in tumor and immune cell compartments. The present proposal study shall therefore explore whether the drugability of DOK1 can be exploited to synergize with clinically-in-use immunotherapeutic antibodies (against PD1/PD-L1) or novel phagocytosis stimulating agents (against CD47) to enforce a tumor-attacking macrophage response.Our translational approach comprises three specific aims: 1) to identify macrophage-specific immune receptor(s) bound by DOK1 using biotin capture assay; 2) to investigate the cellular and molecular mechanisms underlying the immune-regulatory role of DOK1 using gain-of-function and CRISPR/Cas9-knock-out in human macrophage lines and primary cells; 3) to study the (pre)clinical significance of DOK1 expression and macrophage (myeloid lineage) infiltration in GC mouse models and patients’ tissues under therapy. Results are expected to deliver mechanistic insight into the function of DOK1 in macrophages of GC, strengthen our knowledge of cancer immunotherapy and facilitate future effective therapeutic strategies for GC patients.