Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer

Abstract

The ligands for programmed cell death 1 (PD-1), an immunoinhibitory receptor belonging to CD28/cytotoxic T lymphocyte antigen 4 family, are PD-1 ligand 1 and 2 (PD-Ls). Recent reports suggest that the aberrant expression of PD-Ls on tumor cells impairs antitumor immunity, resulting in the immune evasion of the tumor cells. Although an inverse correlation between the expression level of PD-Ls and patients' prognosis has been reported for several malignant tumors, the follow-up period was limited because of the lack of the antibody (Ab) applicable to paraffin-embedded specimens. Here we generated a new Ab against PD-1 ligand 1 (PD-L1) and analyzed the expression level of PD-Ls in human ovarian cancer using paraffin-embedded specimens. Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-1 ligand 2 also had a poorer prognosis, the difference was not statistically significant. A significant inverse correlation was observed between PD-L1 expression and the intraepithelial CD8(+) T lymphocyte count, suggesting that PD-L1 on tumor cells directly suppresses antitumor CD8(+) T cells. Multivariate analysis showed the expression of PD-L1 on tumor cells and intraepithelial CD8(+) T lymphocyte count are independent prognostic factors. The PD-1/PD-L pathway can be a good target for restoring antitumor immunity in ovarian cancer.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Immunohistochemical staining of human ovarian cancer tissues using anti-PD-L1, PD-L2, and CD8+ Abs. (A–H) Representative staining patterns of serous adenocarcinomas with grade 3 (B and F), grade 2 (C and G), and grade 0 (D and H) expression of PD-L1 (B–D) and PD-L2 (F–H) are shown. Placenta (A) and tonsil (E) were used for positive control of PD-L1 and PD-L2, respectively. (I–L) Representative staining patterns of clear cell carcinomas with (J and K) or without (L) CD8+ TILs are shown. Arrows and arrowheads in K indicate intraepithelial and stromal CD8+ TILs, respectively. In I, spleen was used for positive control of CD8+. (Original magnification: ×200 for A–J and L, ×400 for K.)

Fig. 2.

Overall survival analyses of patients with ovarian cancer according to the expression of PD-Ls and the presence of tumor-infiltrating CD8+ T lymphocytes. (A and B) Kaplan–Meier curves according to high or low expression of PD-L1 (A) and PD-L2 (B). (C) Kaplan–Meier curves according to combination of expressions of PD-L1 and PD-L2. (D and E) Kaplan–Meier curves according to positive or negative intraepithelial (D) and stromal (E) tumor-infiltrating CD8+ T cells. (F) Correlation between PD-L1 expression and intraepithelial CD8+ T lymphocytes.

Fig. 3.

Progression-free survival analyses of patients with ovarian cancer based on the expression of PD-Ls and the presence of tumor-infiltrating CD8+ T lymphocytes. (A and B) Kaplan–Meier curves according to expressions of PD-L1 (A) and PD-L2 (B). (C and D) Kaplan–Meier curves according to intraepithelial (C) and stromal (D) CD8+ T cells. The y axes represent progression-free survival (PFS).