Dexamethasone suppresses immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways

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.

Glucocorticoid and PD-1 Cross-Talk: Does the Immune System Become Confused?

“…As previously mentioned, PD-L1 is also upregulated in cancer cells by pro-inflammatory cytokines, such as IFNγ, TNF-α, and IL-6 [ 125 , 126 , 127 ]. Surprisingly, recent data suggest that treating tumor cell lines with GC promotes anti-tumor activity by decreasing PD-L1 expression [ 128 ]. In contrast, GCs induce PD-L1 expression in human DCs through transcription of a GR target gene, GC-induced leucine zipper (GILZ).…”

Repurposing glucocorticoids as adjuvant reagents for immune checkpoint inhibitors in solid cancers

“…The molecular mechanism may be related to the regulation of PI3 and S100A8 6 . Xiang et al 1 also adopted this strategy; they identified a group of compounds that may simultaneously inhibit PD-L1 and IDO1, and among them, dexamethasone was the optimal drug. The strategy of drug repurposing has also played an important role in the COVID-19 pandemic 7 .…”

“…Dexamethasone-mediated transcriptional suppression of PD-L1 and IDO1 depended on the nuclear translocation of the GR/STAT3 complex. Their study suggested that dexamethasone could be used as a sensitization reagent for immune checkpoint inhibitors 1 .…”

“…Theoretically, combination therapy for dual targets should increase the therapeutic effect, but the immune-related adverse events caused by multi-type immune checkpoint inhibitors should not be ignored 12 . To determine whether solid cancers are suitable for combination therapy of dual-targets, Xiang et al 1 conducted correlation analyses of multiple immune evasion-related genes including BTLA , VISTA , CD160 , PD-L1 , CTLA4 , IDO1 , LAG3 , LGALS9 , TNFRSF14 , and VTCN1 , and PD-L1 and IDO1 showed the strongest correlations. High coefficients were found in gastric cancers and colorectal carcinomas.…”

“…Some oncologists warn that glucocorticoids might affect or even weaken the therapeutic efficacy of PD-1 inhibitors. Recently, Xiang et al 1 identified drugs that could target the dual-target of PD-L1/IDO1, and published their finding of “Dexamethasone suppresses immune evasion by inducing GR/STAT3 mediated downregulation of PD-L1 and IDO1 pathways” in Oncogene , a leading international oncology journal. Clinicians, especially oncologists, are interested in knowing what types of cancers are indicators of the drug and what dosage of dexamethasone might be appropriate for assisting cancer immune therapy.…”