Abstract
T cell exhaustion plays critical roles in tumor immune evasion. Novel strategies to suppress immune evasion are in urgent need. We aimed to identify potential compounds to target T cell exhaustion and increase response to immune checkpoint inhibitors (ICIs). Differentially expressed genes (DEGs) were identified between tumors with different immune evasion potential by comparing the transcriptome data. DEGs were then analyzed in the Connectivity Map (CMap) platform to identify potential compounds to increase response to ICIs. Gene set enrichment analysis, LDH release assay, Chromatin immunoprecipitation (ChIP), and Co-IP were performed to explore the potential mechanisms in vitro. Patients derived organoids and humanized xenograft mouse model were utilized to validate the finding ex vivo and in vivo. We identified 25 potential compounds that may play critical roles in regulating tumor immune evasion. We further pinpointed a specific compound, dexamethasone, which shows potent anti-tumor effect in multiple cancer cell lines when cocultured with T cells. Dexamethasone can suppress T cell exhaustion by decreasing the activity of two immune checkpoints simultaneously, including PD-L1 and IDO1. Functional study shows dexamethasone can increase the sensitivity of ICIs in coculture system, 3D organoid model and humanized mouse model. Mechanism study shows dexamethasone mediated transcriptional suppression of PD-L1 and IDO1 depends on the nuclear translocation of GR/STAT3 complex. These findings demonstrate dexamethasone can suppress immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways.