Background
Cervical cancer is the fourth most common malignancy and the fourth leading cause of cancer-related deaths in females globally [
1]. In 2018, it is estimated that 569,847 new cases of cervical cancer are diagnosed and 311,365 cases died from this disease worldwide [
1]. With the improvement of new diagnostic techniques and therapeutic strategies, the incidence rates of cervical cancer have declined significantly in developed countries, however, the mortality is still high in developing countries. Approximately 90% of cervical cancer deaths occurred in low income and middle-income countries (LMIC) [
2]. Although several prognostic biomarkers have been identified, such as lymph node status, tumor size and tumor stage, those biomarkers lack specificity and sensitivity for accurate prediction. Therefore, it is urgently needed to identify many novel and feasible prognostic markers to guide personalized treatment and predict survival outcomes of cervical cancer patients.
Programmed death-ligand 1 (PD-L1 or B7-H1) is the major ligand for programmed cell death protein 1 (PD-1). PD-L1 is expressed in immune cells, including activated T cells, B cells, dendritic cells, macrophages, and various tumor cells [
3]. Normally, PD-L1 expression maintains the homeostasis of the immune response. In the healthy immune system, the activation of the PD-1/PD-L1 pathway can limit autoimmunity and inhibit the activity of T lymphocytes under an inflammatory response to infection [
4]. In tumor microenvironment, cancer cells and infiltrating immune cells express PD-L1, which binds to PD-1 on T cells and then suppress the proliferative and effector responses of T cells [
5,
6]. The prognostic value of PD-L1 in various have been investigated, such as breast cancer [
7], non-small cell lung cancer [
8], pancreatic cancer [
9], renal cell carcinoma [
10], and gastric cancer [
11]. However, the prognostic value of PD-L1 in cervical cancer is still conflicting [
12‐
15]. Therefore, we collected eligible data and conducted a meta-analysis to reveal the prognostic and clinical significance of PD-L1 in cervical cancer.
Discussion
The present meta-analysis is the first to evaluate the association between PD-L1 overexpression and survival in patients with cervical cancer. In this study, we pooled the data from 7 eligible studies with 783 patients and found that PD-L1 was a significant prognostic factor for poor OS, but not for PFS. Further subgroup analysis revealed that PD-L1 overexpression had enhanced prognostic function of poor OS in Asian patients, moreover, PD-L1 also indicated poor PFS in Asian patients. Nevertheless, the correlation of PD-L1 and several clinicopathological features were not statistically significant, which might imply the clinical roles of PD-L1 in cervical cancer diagnosis.
PD-L1 is an important immune regulatory molecule that was reported to be critically involved in the immune escape mechanism of various cancer cells [
24]. In many solid tumors, the overexpression of PD-L1 can lead to immunosuppressive tumor microenvironment and prevent cell-mediated lysis. In addition, the expression of PD-1 in tumor infiltrating lymphocytes is another key point of immune escape mediated by PD-1/PD-L1 [
25]. Interaction of PD-1/PD-L1 results in blocking T cell activation and inhibiting TCR signal transduction and CD28-CD80 co-stimulation [
26]. PD-L1 is also expressed in activated immune cells including dendritic cells, macrophages, B cells, T cells and natural killer cells [
27].
Previous studies also investigated the prognostic role of PD-L1 in various solid tumors. A recent study [
28] demonstrated that expression level of PD-L1 was associated with the OS in gastric cancer (HR = 1.46, 95% CI = 1.08–1.98, p = 0.01). A previous work conducted by Ni et al. also showed that the pooled HR of (1.34, 95% CI 1.02–1.65, p = 0.01) indicated the association of PD-L1 expression with OS in colorectal cancer patients [
29]. Additionally, Ni’s study also reported the expression of PD-L1 was positively correlated with the lymph node metastasis in colorectal cancer [
29]. The prognostic value was also presented in other solid malignancies including prostate cancer [
30], esophageal squamous cell carcinoma [
31], glioma [
32], Osteosarcoma [
33], and non-small cell lung cancer [
34]. The results of the present meta-analysis were in line with the results of other types of cancer. The present study is the first meta-analysis on PD-L1 and cervical cancer to date. Previous meta-analyses [
35,
36] on PD-L1 and survival in solid tumors only included one study [
12] of cervical cancer, the results provided limited information on the prognostic value of PD-L1 in cervical cancer. Therefore, our meta-analysis was comprehensive and convincing. A recent study [
37] systematically reviewed the present and ongoing clinical researches on PD-1/PD-L1 inhibitors in cervical cancer. The patients showed favorable objective response rate (ORR) and disease control with PD-1/PD-L1 inhibitors treatment. We highlight the importance of survival as the primary evaluation endpoint in clinical trials on PD-1/PD-L1 inhibitors in cervical cancer. Furthermore, in the present study, our results that PD-L1 overexpression predicts worse OS might provide implications for future clinical design and assessment.
There are some limitations to this study that should be acknowledged. First, the sample size was relatively small. Although 7 studies were included for analysis, the total sample size was 783, the limited amount may compromise the generality of the results. Second, only articles published in English and Chinese were included in this meta-analysis. Because of our restriction of availability to articles published in other languages, the studies from other countries may be neglected. Third, there may be inconsistent data in the included studies, as they used different cutoff values for identifying PD-L1 overexpression.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.