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.