Expression of PD-1, PD-L1 and PD-L2 is associated with differentiation status and histological type of endometrial cancer

Abstract

Endometrial cancer (EC) is the most frequent gynecological malignancy and a major cause of morbidity and mortality for women worldwide. Programmed cell death protein 1 (PD-1) and its ligands programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) have been well studied in lung cancer, melanoma and renal-cell cancer. However, few studies have been performed in EC. The purpose of the present study was to assess the expression of PD-1, PD-L1 and PD-L2 in 35 human normal endometrial tissue samples and 75 human EC tissue samples using immunohistochemical staining. It was found that 61.3% of ECs were positive for PD-1 staining, which was almost exclusively found in the tumor-infiltrating immune cells. By contrast, PD-1 was not expressed in the tumor cells or normal endometrial tissues. It was also found that 14.3% of normal endometria and 17.3% of EC tissues were positive for PD-L1 expression, while 20.0% of normal endometrium and 37.3% of EC tissues were positive for PD-L2 expression; however, there was no statistically significant difference between the normal endometrium and EC tissues. PD-1 expression in the tumor-infiltrating immune cells was more frequently found in the moderately and poorly-differentiated ECs and non-endometrioid (type II) ECs than in the well-differentiated ECs and endometrioid (type I) ECs. Similarly, PD-L1 and PD-L2 expression in the tumor-infiltrating immune cells was more frequently found in the moderately and poorly-differentiated ECs and type II ECs than in the type I ECs. The present findings indicate a possible better outcome for future treatment with anti-PD-1 or anti-PD-L1 antibody-based therapies against these subgroups of endometrial cancers with frequent expression of the PD-1/PD-L1/PD-L2 axis.

Keywords: PD-1; PD-L1; PD-L2; endometrial cancer; immunohistochemistry.

Figure 1.

Representative photomicrographs of immunohistochemical staining. Arrows indicate the positively stained normal epithelial or tumor epithelial cells. Arrowheads indicate the positively stained tumor-infiltrating immune cells. Original magnification, ×400. Scale bar, 20 µm. AC, adenocarcinoma; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2.

Figure 2.

Correlation analysis of PD-1 and PD-L1 or PD-L2 expression. Correlation between PD-1 and PD-L1 scores in the (A) tumor cells and (B) immune cells. Correlation between PD-1 and PD-L2 scores in the (C) tumor cells and (D) immune cells. The expression levels are indicated by Allred scores and assessed by Spearman's correlation coefficient between two proteins. PD-1 expression was only found in the tumor-infiltrating immune cells. PD-L1 and PD-L2 expression was found in the tumor cells and infiltrating immune cells, which was assessed separately. A number of data points are identical, and therefore overlap in each panel. PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2.