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

Zhen Xiang,Yingyan Yu,Zhijun Zhou,Ranlin Yan,Wenjun Hu,Shuzheng Song,Jun Li,Zhenggang Zhu,Jun Ji,Wei Cai,Zhen Zhang,Lu Zang,Jiexuan Wang,Min Li

doi:10.1038/s41388-021-01897-0

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.

Highlights

T cell immunity against cancers is regulated by co-stimulatory signals and co-suppressive signals
The coefficient of two probes for PD-L1 were 0.675 and 0.502 in GC, (P < 0.05), and were 0.224 and 0.354 in CRC (P = 0.08 and P < 0.05, respectively) (Fig. 1A, Supplementary Fig. S1A). We further validated these findings in pan-cancer analysis in The Cancer Genome Atlas (TCGA) database and found the correlation coefficients of PD-L1 and IDO1 in GC and CRC patients’ tissues were 0.701 (P < 0.001) and 0.783 (P < 0.001), respectively (Fig. 1B)
Since the co-expression of PD-L1 and IDO1 was strongest in GC and CRC, we further analyzed the transcriptomic data of 38 GC cell lines and 61 CRC cell lines in Cell Line Encyclopedia (CCLE) database

Summary

Introduction

T cell immunity against cancers is regulated by co-stimulatory signals and co-suppressive signals. The co-suppressive signals are called immune checkpoints, which weaken T cell functions and play critical roles in tumor immune escape [1]. Several US FDA approved immune checkpoint inhibitors (ICI), including Ipilimumab (anti-CTLA4), Pembrolizumab and Nivolumab (anti-PD1/PD-L1) have impressive anti-tumor effect in a subset of tumors [10]. Wang et al found that LAG-3 and its novel ligand fibrin 1 (FGL1)/LAG-3 functions as new immune checkpoint pathway independent of the PD-1/PD-L1 pathway, and may be new target of cancer resistant to anti-PD1 treatment [12]. Targeting multiple immune checkpoints may be a promising strategy to overcome immune checkpoint inhibitors and acquired more anti-tumor effects in cancers [1]

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Conclusion