C-Myb facilitates immune escape of esophageal adenocarcinoma cells through the miR-145-5p/SPOP/PD-L1 axis.

Lan Zhang,Feng Wang,Xianzheng Gao,Jing Han,Yunfei Li,Xiaohui Wang,Shenglei Li

doi:10.1002/ctm2.464

Abstract

Esophageal adenocarcinoma (EAC), a subtype of esophageal carcinoma, is a severe health problem associated with high death rate and poor prognosis. Immunotherapy has proven to be effective in many solid tumors, including EAC, but immune escape blocks its effectiveness. Thus, we explored the mechanisms and functional role of c‐Myb in immune escape of EAC cells. Clinical EAC tissues were collected for determining the expression of c‐Myb, speckled POZ protein (SPOP), and miR‐145‐5p. Functional assays were then performed to detect the interactions between c‐Myb and SPOP as well as between SPOP and miR‐145‐5p. EAC cell invasion and migration were assessed. Next, T cells were sorted and cocultured with EAC cells with different treatments followed by detection of T‐cell viability. In addition, a mouse model of EAC was constructed for relevant in vivo assays. c‐Myb and miR‐145‐5p were highly expressed and SPOP had low expressions in EAC. c‐Myb activated the transcription of miR‐145‐5p, which in turn targeted SPOP. Further, SPOP accelerated the ubiquitination of PD‐L1 to enhance its expression. Overexpression of PD‐L1 suppressed T‐cell functions and promoted proliferative and migrative abilities of EAC cells to induce immune escape. The above findings were also confirmed in the ECA mouse model in vivo. Our findings uncovered that c‐Myb can promote the immune escape of EAC cells by favoring the transcription of miR‐145‐5p and inhibiting SPOP‐dependent ubiquitination and degradation of PD‐L1, thus, presenting new target for EAC adjunct therapy.

Highlights

Esophageal adenocarcinoma (EAC) is known as an aggressive malignancy with high mortality.[1]
EAC is a severe health threat with increasing incidence, and it is often diagnosed at advanced stage, such that its FIGURE 1 0 Graphical Abstract. c-Myb can up-regulate miR-145-5p expression and inhibit the speckled POZ protein (SPOP)-mediated ubiquitination and degradation of programmed death ligand 1 (PD-L1) to strengthen of EAC cells through the SPOP/PD-L1 pathway prognosis remains dismal despite optimal treatment.[33]
Recent studies have proposed that immunotherapy could be effective for treating gastroesophageal adenocarcinoma, which is in the EAC disease spectrum.[34]

Summary

Introduction

Esophageal adenocarcinoma (EAC) is known as an aggressive malignancy with high mortality.[1] Gastroesophageal reflux disease, obesity, tobacco smoking, and Barrett’s esophagus are risk factors for EAC.[2] Among these factors, Barrett’s esophagus is deemed to be the precursor lesion of this neoplasm.[3] EAC is characterized by male predominance, increasing incidence globally, lack of methods for early detection, and poor prognosis.[4] Recently, immunotherapy has been developed as an innovative, promising treatment measure for many solid tumors including EAC.[5] immune escape is implicated in cancer progression, and tumors express multiple mechanisms to stimulate their immune escape, which remains a primary barrier to successful immunotherapy for cancers.[6,7] In order to enhance the immunotherapeutic efficacy for EAC, we explored in this article potential immune escape mechanisms of EAC cells

Results

Discussion

Conclusion