Ovarian cancer is reported as the sixth most common cancer and seventh most leading cause of cancer-associated death among women worldwide [1]. Additionally, ovarian cancer is known to be the second most common gynecological cancer and leading cause of gynecological cancer-related death in the western world [1]. Majority of the patients with ovarian cancer are initially diagnosed at an advanced stage [International Federation of Gynecology and Obstetrics (FIGO) stage III] due to the lack of clinical appearance. Treatment options for these patients continue to be surgery and platinum-based cytotoxic chemotherapy with five-year survival rates of less than 20% [2].

Programmed cell death 1 (PD-1) receptor belongs to the B7-CD28 family of costimulatory receptors. PD-1 is expressed on the surface of T, B, and Natural Killer (NK) cells and has been shown to play key roles in their activation and apoptosis. Programmed cell death ligand-1 (PD-L1) is one of the ligands of PD-1 that is expressed on both tumor and immune cells such as dendritic cells (DCs) or macrophages. Typically, neoantigens produced by tumor cells are recognized by DCs, which further activate cytotoxic T cells. Activated T cells then infiltrate the tumor environment, bind to cancer cells, and release cytokines that trigger apoptosis in target cancer cells. To escape such anti-tumor mechanism, tumor cells have been observed to often overexpress PD-L1 that binds to PD-1 receptors on the activated T cells, thereby inhibiting cytotoxic T cells. Thus, PD-L1 has been known to be part of a crucial immunological escape mechanism, which promotes tumor cell growth, proliferation, and metastasis [3,4]. However, there are conflicting reports on the relationship between PD-L1 expression and prognosis in ovarian cancer. For instance, Hamanishi et al. [5] reported that PD-L1 expression was associated with poor prognosis in ovarian cancer; however, no relationship between PD-L1 expression and prognosis of ovarian cancer was observed by Mills et al. [6]. Recently, a meta-analysis on PD-L1 expression and prognosis in ovarian cancer has been published in 2018 [7]. This meta-analysis found that PD-L1 expression may be a negative predictor for prognosis of patients with ovarian cancer from Asian countries, while a promising positive predictor for non-Asian patients with ovarian cancer. To gain further clarity on the relationship between PD-L1 expression and ovarian cancer progression, we conducted the present meta-analysis after contemplating high-quality articles that have been recently published.

PD-1 is a member of the CD28 costimulatory receptor superfamily. PD-1 transmits inhibitory signals that abrogate T cell receptor-mediated activating signals, thereby preventing further antigen-mediated activation of T-cells. One of its ligands, known as PD-L1 or CD274, is mainly expressed on the surface of tumor cells and antigen-presenting cells in many solid malignancies [18,19]. In addition to tumor cells, high expression levels of PD-L1 have been observed in human tumor-associated antigen-presenting cells, which includes tumor environment-associated DCs, tumor-draining lymph node DCs, macrophages, fibroblasts, and T cells [19,20,21]. PD-L1 is an important immune regulatory factor, and as a receptor for PD-1, it plays a key role in the immune escape mechanism of cancer cells. PD-L1 specifically binds to the PD-1 receptor of T cells and impairs the activation and differentiation of T cells. Tumor-infiltrating immune cells have been shown to induce cytokines such as interferons and vascular endothelial growth factors that upregulate PD-L1 expression [22,23,24,25]. PD-L1 upregulation is known to regulate various intracellular signaling pathways both at the transcriptional and translational levels. Additionally, this upregulation has been reported to alter the production of various pre-inflammatory factors and cytokines that are secreted in the tumor microenvironment [26,27]. Therefore, PD-L1 overexpression may potentially influence cancer progression and be associated with poor prognoses. Studies on the expression, regulation, and function of the PD pathway in human cancer microenvironment have provided scientific rationales that have directly supported the current clinical application for blocking the PD pathway [18,20]. Moreover, PD-L1 is known to be expressed and associated with the prognosis of many human cancers such as lung [28], breast [29], hepatocellular [30], cervical [31], and ovarian cancers [8,23,32].

Since PD-1/PD-L1 pathway is suggested to play a pivotal role in the immune escape mechanism and growth of cancer cells [4,33], the relationship between PD-L1 expression and prognosis of ovarian cancer has markedly attracted several researchers and clinicians. Previous reports [34,35,36] have suggested the crucial role of PD-1/PD-L1 inhibition in ovarian cancer treatment. Furthermore, some studies have proposed that PD-L1 may not only be a good therapeutic target but also a prognostic biomarker for ovarian cancer [5,9,10,11,15,17]. However, other studies have yielded discrepant results. Thus, the issue still remains controversial concerning ovarian cancer. A previous meta-analysis that investigated the association between PD-L1 expression and prognosis of ovarian carcinoma found that PD-L1 expression is a poor-prognosis biomarker in Asian populations; however, it is a good-prognosis biomarker in non-Asian patients with ovarian cancer [7].

In this meta-analysis, we included 11 studies (13 comparisons). From the selected studies, 11 comparisons were found analyzing the relationship between PD-L1 expression and OS of patients with ovarian cancer, while 6 comparisons were found analyzing the relationship between PD-L1 expression and PFS in ovarian cancer. Overall, our meta-analysis showed that PD-L1 expression was not associated with OS or PFS of patients with ovarian cancer. As high heterogeneity was observed among the included studies, we performed subgroup analysis to investigate the source of heterogeneity. We found that in Asian patients, PD-L1 expression was not associated with OS in ovarian cancer (HR, 0.77; 95% CI, 0.66-0.89; P=0.59; I²=0%). However, in non-Asian patients with ovarian cancer, high PD-L1 expression was observed to increase the risk of OS (HR, 1.26; 95% CI, 1.07-1.48; P=0.01; I²=59%). Intriguingly, our data differed from the conclusions of the previous meta-analysis published in 2018 [7]. Furthermore, our meta-analysis revealed that PD-L1 expression was associated with histology, tumor stage in OS of patients with ovarian cancer. In clinical studies, PD-L1 expression in cancer was mostly studied at the protein level using IHC. However, there are limitations in PD-L1 IHC standardization that may end up with discordant results. While reviewing the included articles, we found that the PD-L1 cut-off point was different in each study. Thus, it is possible that the variations in the cut-off value and antibodies of PD-L1 might have caused the heterogeneity. Moreover, the previous studies revealed that patients with IHC-positive tumors may not respond to treatment [37].

Our meta-analysis had certain limitations. For example, at the literature review level, we cannot exclude the possibility that despite our best efforts, some relevant studies may have been inadvertently excluded or not found in our queried databases using the selected search terms. Moreover, only studies published in English language journals were included in our meta-analysis, which introduces a selection bias. We are aware of the fact that although our qualitative assessment of the primary studies would have revealed certain inherent biases, it would have not encapsulated the aggregate effect of any potential biases from the pooled HRs.

In summary, our updated meta-analysis suggests that PD-L1 expression is not associated with OS or PFS of patients with ovarian cancer. Due to high heterogeneity, the data are not highly reliable. Furthermore, PD-L1 expression was observed to be associated with histological type or FIGO stage of ovarian cancer, specifically with non-Asian patients with this disease. Thus, additional research with prospective large-cohort studies involving diverse population should be conducted to conclusively demonstrate whether PD-L1 expression has a significant prognostic value in ovarian cancer.