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.

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).