Co-Expression with Membrane CMTM6/4 on Tumor Epithelium Enhances the Prediction Value of PD-L1 on Anti-PD-1/L1 Therapeutic Efficacy in Gastric Adenocarcinoma.

Ziqi Wang,Rong Jin,Jing Su,Zhi Peng,Qing Ge,Ting Li,Pingzhang Wang,Zixia Guo,Lin Shen,Qiyao Liu,Merey Menatola

doi:10.3390/cancers13205175

Abstract

Simple SummaryImmunotherapeutic efficacy is low even in PD-L1 positive patients with advanced gastric adenocarcinoma. Based on the results of 6-color multiplex immunofluorescence staining of the gastric tumor tissues in tissue array and 48-case pre-immunotherapy patients, a better prognostic value was found in the membrane co-expression of CMTM6/4 and PD-L1 in tumor epithelial cells than PD-L1 alone. The membrane co-expression of CMTM6/4 and PD-L1 can be used as a valuable tool for precision pre-immunotherapy patient screening in gastric adenocarcinoma.Anti-PD-1/L1 immunotherapy has been intensively used in heavily treated population with advanced gastric adenocarcinoma. However, the immunotherapeutic efficacy is low even in PD-L1 positive patients. We aimed to establish a new strategy based on the co-expression of CMTM6/4 and PD-L1 for patient stratification before immunotherapy. By analyzing the data obtained from TCGA and single-cell RNA sequencing at the mRNA level, and 6-color multiplex immunofluorescence staining of tumor tissues in tissue array and 48-case pre-immunotherapy patients at the protein level, we found that CMTM6/4 and PD-L1 co-expressed in both epithelial and mesenchymal regions of gastric adenocarcinoma. The tumor tissues had higher levels of CMTM6/4 expression than their adjacent ones. A positive correlation was found between the expression of CMTM6/4 and the expression of PD-L1 in tumor epithelium. Epithelial co-expression of CMTM6/4 and PD-L1 in gastric tumor region was associated with shorter overall survival but better short-term response to anti-PD-1/L1 immunotherapy. Thus, we developed a predictive model and three pathological patterns based on the membrane co-expression of CMTM6/4 and PD-L1 in tumor epithelial cells for pre-immunotherapy patient screening in gastric adenocarcinoma.

Highlights

Introduction conditions of the Creative CommonsAnti-PD-1/L1 immunotherapy has been used as a later-line therapy or first-line therapy in combination with chemotherapy for gastric cancer (GC), but with mixed therapeutic results
We found that the co-expression of CMTM6/4 and PD-L1 in gastric tumor epithelial cells significantly correlated with poor prognosis and may function as a pivotal predictor of response in GC patients receiving anti-PD1/L1 immunotherapy
We further examined the association of CMTM6/4 expression with the tumor burden and found that high levels of CMTM6 in the epithelial (Figure 3C) and mesenchymal (Figure 3D) regions were positively associated with the tumor burden and cell proliferation (Ki-67)

Summary

Introduction

Anti-PD-1/L1 immunotherapy has been used as a later-line therapy or first-line therapy in combination with chemotherapy for gastric cancer (GC), but with mixed therapeutic results. KEYNOTE-012, KEYNOTE-059, and KEYNOTE-158 studies demonstrated anti-tumor activity and clinical benefit [1,2,3] while both KEYNOTE-061 and JAVELIN Gastric 300 studies failed to show the superiority of immunotherapy over chemotherapy [4,5]. PD-L1 expression is one of the primary biomarkers in predictive stratification of patients receiving anti-PD-1/L1 therapy [1,6,7]. PD-L1 expression was reported in 25–65% of GC patients by histochemical staining [8], while the high PD-L1 positivity did not correlate well with the response rate of anti-PD-1/L1 therapy in several clinical trials [2,5,9,10]. As the surface expression level of PD-L1 is regulated by multiple factors, investigating the molecules that promote the expression and/or stability of PD-L1 is important for the optimization of patient selection

Objectives

Methods

Conclusion