MTDH associates with m6A RNA methylation and predicts cancer response for immune checkpoint treatment

Fen Zhang,Huimei Huang,Yuexiang Qin,Changhan Chen,Li She,Juncheng Wang,Donghai Huang,Qinglai Tang,Yong Liu,Gangcai Zhu,Xin Zhang

doi:10.1016/j.isci.2021.103102

Abstract

SummaryImmune checkpoint blockade (ICB) persistently provides a prognosis improvement but only in a small fraction of patients with cancer due to immunotherapy resistance induced by the consecutive activated oncogenic pathways, including MAPK, Akt, and WNT pathway partially driven by Metadherin (MTDH). However, there is no study to investigate the potential role and mechanisms of MTDH in ICB-treated cancers. Here, we systematically explored the cohorts from The Cancer Genome Atlas (TCGA) and independent cancer cohorts. Elevated MTDH expression was founded to associate with a worse overall survival and poorer immune response in patients with cancer. Dysregulated tumor-infiltrating immune cells and inhibitory immune checkpoint expression were correlated with MTDH expression. Furthermore, the mutual interactions between epithelial-to-mesenchymal-transition, m6A-RNA-methylation, and MTDH may illustrate the potential mechanisms of MTDH resistant to ICB treatment. Although more designed experiments and trials are needed in the future, targeting MTDH may help to overcome immunotherapy resistance in a wide range of cancers.

Highlights

Cancer ranks as a leading cause of death and a massive barrier to increasing life expectancy globally in decades (Sung et al, 2021)
SUMMARY Immune checkpoint blockade (ICB) persistently provides a prognosis improvement but only in a small fraction of patients with cancer due to immunotherapy resistance induced by the consecutive activated oncogenic pathways, including MAPK, Akt, and WNT pathway partially driven by Metadherin (MTDH)
We systematically explored the cohorts from The Cancer Genome Atlas (TCGA) and independent cancer cohorts

Summary

Introduction

Cancer ranks as a leading cause of death and a massive barrier to increasing life expectancy globally in decades (Sung et al, 2021). Surgery and chemoradiotherapy have been considerably prolonged life of patients with cancer for many decades. The improvement of overall outcome for patients with cancer hit a plateau until immune checkpoint blockade (ICB) developed in recent years. Reports of patients with cancer achieving complete remissions are accumulating, be that as it may, the proportion of non-responders to ICB treatment remains in major. Except for immunosuppressive microenvironment (such as Tregs and MDSCs) and insufficient tumor immunogenicity (such as impaired dendritic cell and MHC dysfunction), activations of oncogenic pathways, including MAPK, PI3K, and WNT/b-catenin pathway, are reported to drive carcinogenesis and ICB resistance (Lei et al, 2020). Tumor-intrinsic oncogenic pathways for PD1/PD-L1 blockade resistance should not be undermined (Lei et al, 2020)

Results

Discussion

Conclusion