PD-L1 Expression and CD8+ Tumor-infiltrating Lymphocytes in Different Types of Tubo-ovarian Carcinoma and Their Prognostic Value in High-grade Serous Carcinoma

Abstract

The prevalence and significance of programmed death-1 ligand (PD-L1) expression in different types of tubo-ovarian carcinoma have not been well defined. We evaluated PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density in whole tissue sections of 189 cases of tubo-ovarian carcinoma, including high-grade serous carcinoma (HGSC, n=100), clear cell carcinoma (CCC, n=24), endometrioid carcinoma (EmC, n=40), and mucinous carcinomas (MC, n=25). Using the tumor proportion score (TPS) with a 1% cutoff, PD-L1 expression was present in 21% of HGSC, 16.7% of CCC, 2.5% of EmC, and 4% of MC. Using the combined positive score (CPS) with a cutoff of 1, PD-L1 expression was present in 48% of HGSC, 25% of CCC, 20% of EmC, and 24% of MC. HGSC demonstrated significantly higher CD8+ TIL density than CCC (P=0.013238), EmC (P=0.01341), or MC (P=0.004556). In HGSC, CD8+ TIL density was directly correlated with PD-L1 positivity using either TPS (P=0.0008) or CPS (P=0.00011). Survival analysis of patients with high stage (stage III to IV) HGSC revealed PD-L1 positivity by TPS to be associated with improved progression-free survival (adjusted hazard ratio: 0.4912 vs. 2.036, P=0.0378). Although not statistically significant, a similar trend was observed in overall survival (adjusted hazard ratio: 0.3387 vs. 2.953, P=0.0548). In contrast, with CPS, no significant difference was identified between PD-L1-positive and negative groups in either progression-free survival (P=0.5086) or overall survival (P=0.7823). Neoadjuvant chemotherapy was associated with higher PD-L1 expression by TPS (P=0.00407) but not CPS. No significant difference in PD-L1 expression was detected in tumors from patients with germline BRCA1/2 mutations compared with germline mutation-negative tumors by either TPS or CPS. In conclusion, the prevalence of PD-L1 expression is variable in different types of tubo-ovarian carcinoma and is highest in HGSC. In high-stage HGSC, PD-L1 positivity in tumor cells is associated with an increased immune response and improved survival.

Immunology and Immune Checkpoint Inhibition in Ovarian Cancer – Current Aspects

“…PD-L1 expression was initially studied mostly in tumour cells. In particular, while previous reports showed a significant correlation of PD-L1 tumour cell expression with poor survival 28 , 97 , 99 , other groups demonstrated just the opposite, correlating PD-L1 with improved immune infiltration and prolonged survival 100 , 101 , 102 , 103 , 104 . This may be explained by a general increase in IFN-γ response in these tumours as IFN-γ on the one hand delivers an effective anti-tumour response, on the other hand it is a very potent inducer of PD-L1 expression in ovarian cancer cells 97 , 100 .…”

“…This is somewhat surprising, as clear cell cancers exhibit the best response to PD-1/PD-L1 checkpoint inhibition in current clinical trials, albeit with small case numbers (see below), and illustrates once again that PD-L1 expression per se is not a good predictive marker. BRCA1/2 mutation status did not result in a difference in PD-L1 expression 104 .…”

“…PD-L1-positive tumours are most commonly found among serous carcinomas, significantly more so than in clear cell, mucinous and endometrioid cancers [102,104]. This is somewhat surprising, as clear cell cancers exhibit the best response to PD-1/PD-L1 checkpoint inhibition in current clinical trials, albeit with small case numbers (see below), and illustrates once again that PD-L1 expression per se is not a good predictive marker.…”

“…Die PD-L1-Expression wurde zunächst vor allem auf den Tumorzellen untersucht. Während insbesondere frühere Berichte eine signifikante Korrelation der PD-L1-Tumorzellexpresion mit einem schlechten Überleben zeigten 28 , 97 , 99 , zeigen andere Arbeitsgruppen genau das Gegenteil, und korrelieren PD-L1 mit einer verbesserten Immuninfiltration und einem verlängerten Überleben 100 , 101 , 102 , 103 , 104 . Dies mag sich durch eine generell gesteigerte IFN-γ-Antwort in diesen Tumoren erklären, denn IFN-γ sorgt einerseits für eine effektive Anti-Tumor-Antwort im Ovarialkarzinom, andererseits ist es ein sehr potenter Induktor einer PD-L1-Expression in Ovarialkarzinomzellen 97 , 100 .…”

Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation

“…112 Among the gynaecological malignancies, high grade serous ovarian carcinoma shows the highest expression of PD-L1, and is of particular interest, with some evidence that expression correlates with improved responses to ICIs in high stage disease. 113 There have also been promising early results in HPV related cervical carcinoma. 114…”