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.