Abstract
Background
Programmed death-ligand 1 (PD-L1) was the first identified ligand of programmed death-1 (PD-1). PD-1/PD-L1 interactions inhibit T cell-mediated immune responses, limit cytokine production, and promote tumor immune escape. Recently, many studies have investigated the prognostic value of PD-L1 expression in patients with melanoma. However, the results of these analyses remain a subject of debate. We have therefore carried out a meta-analysis to identify the prognostic role of PD-L1 in melanoma.
Methods
A thorough medical literature search was performed in the databases PubMed, Web of Science, and Embase until October 2019. The pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated to evaluate the correlation between PD-L1 overexpression and prognosis. Publication bias was evaluated using Begg’s test and Egger’s test.
Results
Thirteen articles with 1062 enrolled patients were included in this meta-analysis. High PD-L1 expression did not correlate with overall survival (OS) (HR = 0.93, 95% CI 0.57–1.52, P = 0.781) or progression-free survival (PFS) (HR = 0.82, 95% CI 0.43–1.54, P = 0.535). However, PD-L1 overexpression correlated with the absence of lymph node (LN) metastasis (OR = 0.46, 95% CI 0.22–0.95, P = 0.036). Further, there was no significant relationship between PD-L1 expression and sex (OR = 1.29, 95% CI 0.90–1.84, P = 0.159), age (OR = 0.90, 95% CI 0.51–1.57, P = 0.708), or Eastern Cooperative Oncology Group Performance Status (OR = 0.55, 95% CI 0.06–4.83, P = 0.592).
Conclusions
This meta-analysis suggested that PD-L1 expression did not predict an inferior prognosis in patients with melanoma. However, high PD-L1 expression was associated with absence of LN metastasis in such patients.
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Background
Melanoma is the most fatal form of skin cancer, and the incidence rates continue to increase dramatically [1]. Worldwide, approximately 232,100 new cases of cutaneous melanoma are diagnosed each year, and 55,500 patients die annually [2]. Ultraviolet exposure, skin type, indoor tanning, and a personal history of prior melanoma are risk factors of melanoma [3,4,5]. The most important prognostic factor of melanoma is the BRAF mutational status [6]. The other prognostic factors are American Joint Committee on Cancer (AJCC) melanoma TNM (tumor, node, metastasis) staging [7], Clark level, and Breslow thickness [8], and they are useful for the clinical management of patients with melanoma. In the United States, patients present melanoma at different stages, with 84% of them presenting localized disease, 9% presenting regional disease, and 4% exhibiting distant metastasis [9]. The prognosis for patients with localized disease is promising, with a 5-year survival rate of over 90% [10]. Whereas the prognosis for patients with unresectable stage III–IV tumors is poor, as the 10‐year overall survival (OS) is only 10% to 15% for those patients [1]. In recent years, significant progress has been achieved in the development of targeted therapies and immunotherapy [11, 12]; however, novel prognostic markers are still needed for tailoring personal treatment strategies.
In recent years, immune inhibitory signaling pathways have been recognized to play a pivotal role in the maintenance of an immunosuppressive microenvironment that favors cancer development [13]. One important co-inhibitory pathway is the programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) axis [14]. PD-1 is expressed in a wide range of immune cells, and its expression is induced on effector T‐cells in response to inflammatory signals [16]. Accumulating evidence shows that PD-L1 plays a central role in the regulation of the immune responses in the tumor microenvironment [50]. PD-L1 binds to PD-1 and inhibits T cell proliferation and its cytokine secretion and leads to apoptosis, anergy, and exhaustion of T cells [51]. Therefore, blockade of the PD-1/PD-L1 interaction is an important therapeutic strategy for cancer. Tumor-intrinsic PD-L1 signals can enhance the ability of melanoma cells to proliferate and metastasize [52]. Melanoma has seen the broadest applications and superior responses to anti-PD-L1/PD-1 therapies [53]. Recent studies have demonstrated that anti-PD-L1 antibody induced durable tumor regression and prolonged stabilization of disease in patients with advanced cancer, including non-small cell lung cancer (NSCLC), melanoma, and colorectal cancer [54]. In addition, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone in metastatic melanoma [55]. Therefore, there is rationale to identify PD-L1 as a biomarker for assessing cancer therapeutic responses and survival outcomes in patients with melanoma. The findings of our meta-analysis indicate that PD-L1 may not be helpful in prognosis of melanoma, which may be validated in further large-scale prospective clinical trials.
Many previous studies have investigated the impact of PD-L1 on the prognosis of solid tumors through meta-analyses [56]. Iacovelli and colleagues conducted a meta-analysis of 6 studies and showed that increased PD-L1 expression was an independent prognostic factor in renal cell carcinoma [57]. Another meta-analysis also demonstrated that high PD-L1 expression was a poor prognostic biomarker in patients with non-Hodgkin lymphoma [58]. A meta-analysis of studies that enrolled 721 patients also confirmed the prognostic significance of PD-L1 expression in thyroid cancer [59]. However, some meta-analyses failed to identify a significant prognostic effect of PD-L1 in cancer. For example, Fan’s meta-analysis reported a non-significant relationship between PD-L1 expression and OS in NSCLC [60]. Moreover, a more recent study of 1060 patients indicated that PD-L1 overexpression did not correlate with the poor prognosis of patients with oral squamous cell carcinoma (OSCC) [61]. The results of the current meta-analysis in melanoma were in line with the findings of NSCLC and OSCC [60, 61].
Although this is the first meta-analysis of the association between PD-L1 and the prognosis of melanoma, some limitations need to be noted. First, the heterogeneity among studies cannot be ignored. Patient ethnicity, treatment, follow-up, and other factors could influence survival, which may have contributed to this heterogeneity. Second, the included studies used different monoclonal and polyclonal PD-L1 antibodies for IHC, and the cut-off values were not uniform. Third, all included studies were published in the English language, and absence of including studies published in non-English languages may lead to publication bias.
Conclusions
In summary, this meta-analysis suggested that PD-L1 expression did not predict inferior prognosis in patients with melanoma. However, high PD-L1 expression was associated with absence of LN metastasis. Because of the limitations of our meta-analysis, further large-scale and prospective trials that use a uniform cut-off value of PD-L1 expression are needed to verify our results.
Availability of data and materials
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Abbreviations
- PD-L1:
-
Programmed death-ligand 1
- PD-1:
-
Programmed death-1
- HR:
-
Hazard ratio
- CI:
-
Confidence interval
- OS:
-
Overall survival
- PFS:
-
Progression-free survival
- LN:
-
Lymph node
- AJCC:
-
American Joint Committee on Cancer
- TNM:
-
Tumor, node, metastasis
- IHC:
-
Immunohistochemistry
- EV:
-
Extracellular vesicle
- ICI:
-
Immune checkpoint inhibitors
- ECOG PS:
-
Eastern Cooperative Oncology Group performance status
- NSCLC:
-
Non-small cell lung cancer
- OSCC:
-
Oral squamous cell carcinoma
- PRISMA:
-
Preferred reporting items for systematic reviews and meta-analyses
- NOS:
-
Newcastle–Ottawa Scale
- OR:
-
Odds ratio
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JY, MD, Y Shui, YZ and YM designed the study. ZZ, LJ, KL, JY, MD, and XG performed the literature searches and assessed the quality of included studies. YZ, KL, ZL, and XZ analyzed the data. XG and Y Shi wrote the manuscript. All authors read and approved the final manuscript.
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Yang, J., Dong, M., Shui, Y. et al. A pooled analysis of the prognostic value of PD-L1 in melanoma: evidence from 1062 patients. Cancer Cell Int 20, 96 (2020). https://doi.org/10.1186/s12935-020-01187-x
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DOI: https://doi.org/10.1186/s12935-020-01187-x