Prognostic role of programmed-death ligand 1 (PD-L1) expressing tumor infiltrating lymphocytes in testicular germ cell tumors

Abstract

Purpose: Testicular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs.

Results: PD-L1 positive TILs were found significantly more often in seminomas (95.9% of patients) and embryonal carcinomas (91.0%) compared to yolk sac tumors (60.0%), choriocarcinomas (54.5%) or teratomas (35.7%) (All p < 0.05). TGCTs patients with high infiltration of PD-L1 positive TILs (HS ≥ 160) had significantly better progression-free survival (HR = 0.17, 95% CI 0.09 - 0.31, p = 0.0006) and overall survival (HR = 0.08, 95% CI 0.04 - 0.16, p = 0.001) opposite to patients with lower expression of PD-L1 (HS < 150). PD-1 expressing TILs were not prognostic in TGCTs.

Materials and methods: Surgical specimens from 240 patients with primary TGCTs were included into this translational study. The PD-1 and PD-L1 expression on tumor and TILs were detected by immunohistochemistry using anti-PD-1 and anti-PD-L1 monoclonal antibody. Scoring was performed semiquantitatively by weighted histoscore (HS) method.

Conclusions: The prognostic value of PD-L1 expressing TILs in TGCTs was demonstrated for the first time.

Keywords: prognostic factor; programmed cell death protein 1; programmed death-ligand 1; testicular germ cell tumors; tumor infiltrating lymphocytes.

Figure 1

A. Kaplan-Meier estimates of probabilities of progression-free survival according to PD-L1 expressing tumor infiltrating lymphocytes (TILs); in patients with primary TGCTs (n = 240), Hazard ratio = 0.17, 95% CI 0.09 – 0.31, p = 0.0006, Low HS - low PD-L1 expressing TILs; High HS- high PD-L1 expressing TILs. B. Kaplan-Meier estimates of probabilities of overall survival according to PD-L1 expressing tumor infiltrating lymphocytes (TILs); in patients with primary TGCTs (n = 240), Hazard ratio = 0,08, 95% CI (0.04 – 0.16), p = 0.001, Low HS - low PD-L1 expressing TILs; High HS- high PD-L1 expressing TILs.

Figure 2

A. Kaplan-Meier estimates of probabilities of progression-free survival according to PD-L1 expression on tumor cells and tumor infiltrating lymphocytes (TILs); in patients with primary TGCTs (n = 240), Low HS - low PD-L1 expression; High HS- high PD-L1 expression. A 5-year progression-free survival in groups of patients according to PD-L1 expression in tumor and TILs were as follows: low PD-L1 in tumor and high PD-L1 on TILs: 95.9%; high PD-L1 in tumor and high PD-L1 on TILs: 91.7%; low PD-L1 in tumor and low PD-L1 on TILs: 76.5 %; high PD-L1 in tumor and low PD-L1 on TILs: 72.2%. B. Kaplan-Meier estimates of probabilities of overall survival according to PD-L1 expression on tumor cells and tumor infiltrating lymphocytes (TILs); in patients with primary TGCTs (n = 240), Low HS - low PD-L1 expression; High HS- high PD-L1 expression. A 5-year overall survival in groups of patients according to PD-L1 expression in tumor and TILs were as follows: low PD-L1 in tumor and high PD-L1 on TILs: 100%; high PD-L1 in tumor and high PD-L1 on TILs: 91.7%; low PD-L1 in tumor and low PD-L1 on TILs: 84.5 %; high PD-L1 in tumor and low PD-L1 on TILs :72.2%.

Figure 3. Immunohistochemical detection of programmed death-cell ligand 1 (PD-L1) expression in tumor infiltrating lymphocytes in testicular germ cell tumors

A. Seminoma showed weak focal membranous PD-L1 positivity to negativity (brown colour) with strong cytoplasmic PD-L1 positivity of tumor infiltrating lymphocytes; B. Embryonal carcinoma with PD-L1 negativity and intermediate cytoplasmic PD-L1 positivity of tumor infiltrating lymphocytes; C. Yolk sac tumor with constant weak membranous PD-L1 positivity and strong cytoplasmic PD-L1 positivity of tumor infiltrating lymphocytes; D. Seminoma and tumor infiltrating lymphocytes negative for PD-L1. Original magnification ×40/x400.