Although many studies have investigated the relationship between ESCC patient’s prognosis, clinicopathological characteristics, and PD-L1 expression, the query yielded controversial results. This study examined 139 well-documented ESCC specimens in order to investigate the possible role and clinical significance of PD-L1 expression in locally resectable patients with advanced ESCC. We discovered that there was no association between tumor cells with higher PD-L1 expressions and the clinicopathological features of ESCC patients. The results also showed that higher PD-L1 expressions represented a significant independent prognostic factor for those patients.
Positive PD-L1 expression is usually assessed through the percentage and number of TCs with PD-L1 expression [16–19]. Previous studies have indicated a positive PD-L1 expression rate ranging between 18.4% and 79.7%. ISP was assessed in this study, considering that the positive PD-L1 expression rate might not effectively reflect the intensity of PD-L1 expression. ISP ≥ 3 was viewed as a positive PD-L1 expression. Consequently, the positive PD-L1 expression rate in this study was 40.3%. The difference in the positive PD-L1 expression rate between our study and prior ones can be attributed to the difference in detection methods, reagents, sample size, and evaluation standards.
Previous studies performed by Ohigashi et al. and Ito et al. revealed an association between tumor stage, lymph node status and PD-L1 expression [18, 20]. However, some other studies have suggested that none of the clinicopathological features were associated with PD-L1 expression [17, 21–24]. Our results did not find any association between PD-L1 expression and clinicopathological factors such as age, gender, tumor location, differentiation, and stage of lymph node metastasis.
PD-L1 expression has also been explored as a prognostic predictor for ESCC. Previous reports on the connection between PD-L1 expression and patient’s clinical outcome have yielded controversial results [20, 21, 23, 25–30], with the major studies showing poor prognosis [20, 23, 26–28, 30] and some studies reported opposite results [21, 25, 29]. For the above studies, researchers have used immunohistochemistry to detect PD-L1 expression, and have come to different conclusions. The discrepancies might be related to variations in detection methods, reagent sensitivities, and evaluation criteria. In this study, we also found that high PD-L1 expression is an independent risk factor for poor outcome in patients with resectable locally advanced ESCC.
Additionally, we found that the expression of PD-L1 was significantly associated with poor clinical outcome in patients with earlier stage ESCC (without lymph node metastasis), while there was a lack of associated between PD-L1 expression and DFS or OS in advanced patients(with lymph node metastasis) was seen. This indicated that the prognostic value of PD-L1 expression was limited and not useless in every stages of ESCC. The associations between PD-L1 expression and poor outcome have also been observed in several human cancers, including non-small cell lung cancer (NSCLC) , colorectal cancer , breast cancer , and melanoma . The mechanism by which PD-L1 over-expression leads to a poor prognosis in ESCC patients remains unclear. It may be reasonable to assume that PD-L1 expression in those patients is reflective of the immunosuppressive effect. In the early stages of cancer, the antitumor response is reduced due to immunosuppressive effects of the PD-1 / PD-L1 pathway, thus leading to worse survival. However, in the later stages of cancer, the effect of lymph node metastasis on the patient’s prognosis is far greater than that of PD-L1 expression. Therefore, partially explaining the inconsistencies seen in studies assessing the prognostic role of PD-L1 over-expression in ESCC patients. When addressing conflicting results in survival analyses in the future, researchers should remember to take into consideration the patient’s lymph node status.
The limitations of this study are as follows: firstly, this is a retrospective single centered study, therefore prone to selection bias. Secondly, the study sample is relatively small, making it less reflective. Thirdly, all patients included in this study were patients with stage T3. The correlation between different TNM staging and PD-L1 expression was not analyzed, which might affect the final results. Fourthly, we only examined the expression of PD-L1 in TMA sections. Considering that those sections only capture a small volume of tissue and that tumors may heterogeneously express PD-L1, this might lead to an over or underestimation of the true expression levels of PD-L1 protein.