Prognostic value and clinicopathological characteristics of PD-L1 overexpression in non-Hodgkin lymphoma: a meta-analysis

Non-Hodgkin lymphoma (NHL), accounting for approximately 90% of lymphomas and comprising various subtypes, is a common hematological tumor. NHL is characterized by a series of malignant DNA repair obstacle events and activating proto-oncogene caused by viral or bacterial infection, immune dysfunction and genetic factors, resulting in a wide range of histological appearances and clinical features at presentation, including painless lymphadenopathy, B symptoms (weight loss > 10%, night sweats, body temperature > 38 °C), and so on [1]. The prognoses of NHL patients remain poor, while the 5-year overall survival (OS) rates have improved [2, 3]. Therefore, we posit that there may be other biomarkers potentially influencing the prognosis of NHL.

Programmed cell death ligand 1 (PD-L1), a 40 kDa type 1 transmembrane protein, can activate B, T cells, macrophages, and dendritic cells [4, 5]. It was first found by Chen et al in 1999 [6]. It was reported that PD-L1 co-stimulated T-cell proliferation and interleukin-10 secretion, which was considered to be involved in the negative regulation of cell-mediated immune responses [6]. Under normal physiological conditions, immune checkpoints maintain self-tolerance and protect tissues from damage when the immune system is responding to pathogenic infections [7, 8]. However, PD-L1, bound to programmed cell death 1 (PD-1), inhibits effector T cell function and activates immunosuppressive regulative T-cell function, resulting in tumors escaping under pathological conditions [9‐11]. which is a major mechanism of tumor recurrence and drug resistance [12]. Moreover, clinical research inferred that patients who had overexpression of PD-L1 in tumors had improved clinical outcomes after taking checkpoint blockades [13].

Cumulative studies showed that PD-L1 or PD-1 could be used to determine prognosis in various cancers, such as melanoma, non-small cell lung cancer, kidney cancer [5], and classic Hodgkin lymphoma [14]. Some studies have also assessed the prognostic value of PD-L1 overexpression in NHL. However, the results were quite different. Thus, we aim to identify the problem through performing a meta-analysis.

Our meta-analysis was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15].

This is a meta-analysis designed to investigate the relationship between PD-L1 overexpression and the prognosis of NHL. The association of PD-L1 overexpression with some clinicopathological factors was also evaluated. The pooled HR of 1.40 (95% CI: 0.90–2.19; P = 0.137) was calculated for 2321 patients from 12 studies, potentially indicating no significant correlation between PD-L1 and NHL prognosis. Nevertheless, the result suggested that PD-L1 overexpression was associated with poor prognosis in DLBCL patients. Figure 4 illustrates that patients with B symptoms, IPI scores of 3 to 5 points, and Ann Arbor Stage III or IV possessed overexpression of PD-L1.

Subgroup analysis and meta-regression showed no contribution to the heterogeneity in NHL. However, perhaps some problems contributed to the heterogeneity. Although IHC was used to detect PD-L1 protein in tumor cells in all studies, different studies adopted different procedures [30], antibody clones and thresholds [31]. Vranic et al. [32] suggested that anti-PD-L1 clones SP142 and SP263 exhibit an excellent concordance. Additionally, other confounding factors influence the expression of PD-L1. Studies [33, 34] indicated that anaplastic lymphoma kinase (ALK) up-regulates PD-L1 expression. Research also suggested that STAT3 regulates PD-L1 expression, and it was demonstrated that the inhibitor of STAT3 abrogated the expression of PD-L1 [35, 36]. It was also shown that tumor cells that overexpress PD-L1 protein have been frequently detected in EBV-positive lymphomas [20, 26, 37, 38].

The response to treatment is also not associated with the level of PD-L1 expression. Currently, PD-1 blockades are mostly employed clinically. Some clinical trials [39, 40] showed that patients with B-cell NHL indeed responded well to PD-1 blockades combined with rituximab. Zinzani et al. [41] found that PD-1 blockades used alone also benefited B-cell NHL patients. Two studies [42, 43] showed that PD-1 blockades helped relapsed or refractory NHL patients increase complete response rate. However, the level of PD-L1 expression in patients was quite different, and PD-L1was not even detected in some patients. These findings indicate that the level of PD-L1 expression is not associated with the prognosis of NHL patients.

Nevertheless, recent studies have uncovered the concrete functional mechanism of PD-L1 in DLBCL. PD-L1, bound to PD-1, caused phosphorylation of AKT, which urge m-TOR to activate its downstream molecules, such as P43-BP1 and P-P70S6K, finally resulting in proliferation and progression of malignant cells [19, 44, 45]. Theoretically, this explains why overexpression of PD-L1 causes short OS in DLBCL patients. Unfortunately, in other NHL subtypes, there is currently no such theory.

To the best of our knowledge, Zhao et al. [46] performed the first meta-analysis, which included 9 studies, to explore the relationship between PD-L1 overexpression and prognosis in NHL patients and concluded that PD-L1 overexpression has an association with poor prognosis in NHL and DLBCL but not with natural killer/T-cell (NK/T) lymphoma. We brought 12 studies with a total of 2321 patients into our meta-analysis and obtained conclusions that are different from Zhao et al.’s. In DLBCL and NK/T lymphoma (data not show), we reached the same conclusion as did Zhao et al. Yet, our conclusion regarding the overall result of NHL differs from that of Zhao et al’s due to our having included three more studies than they did. We also adopted two tools to conduct meta-analysis and did sub-analysis.

Several limitations, however, must be considered in interpreting our findings. First, the total sample size of the included studies was small. Second, other clinicopathological factors—such as EBV infection, tumor size, and central neutral system invasion—were not included in the analysis due to insufficient materials. Third, although we performed subgroup analysis by cut-off value, we did not know the best cut-off value for stratification of NHL patients in clinical management.

In conclusion, our pooled results showed that overexpression of PD-L1 was not associated with OS in NHL patients; rather, it was associated with the subtype of DLBCL, indicating that PD-L1 could perhaps predict the prognosis of DLBCL. Furthermore, PD-L1 overexpression was associated with the clinicopathological factors of B symptoms, IPI score, and Ann Arbor Stage. Nevertheless, studies on other specific NHL subtypes using standardized immunological tests are needed to further explore the relationship between PD-L1 overexpression and prognosis of NHL.