CD70 and PD‐L1 (CD274) co‐expression predicts poor clinical outcomes in patients with pleural mesothelioma

Abstract

AbstractDiffuse pleural mesothelioma (PM) is a highly aggressive tumour typically associated with short survival. Recently, the effectiveness of first‐line immune checkpoint inhibitors in patients with unresectable PM was reported. CD70–CD27 signalling plays a co‐stimulatory role in promoting T cell expansion and differentiation through the nuclear factor κB (NF‐κB) pathway. Conversely, the PD‐L1 (CD274)–PD‐1 (PDCD1) pathway is crucial for the modulation of immune responses in normal conditions. Nevertheless, pathological activation of both the CD70–CD27 and PD‐L1–PD‐1 pathways by aberrantly expressed CD70 and PD‐L1 participates in the immune evasion of tumour cells. In this study, 171 well‐characterised PMs including epithelioid (n = 144), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, PD‐L1, and immune cell markers such as CD3, CD4, CD8, CD56, PD‐1, FOXP3, CD68, and CD163. Eight percent (14/171) of mesotheliomas simultaneously expressed CD70 and PD‐L1 on the tumour cell membrane. PMs co‐expressing CD70 and PD‐L1 contained significantly higher numbers of CD8+ (p = 0.0016), FOXP3+ (p = 0.00075), and CD163+ (p = 0.0011) immune cells within their microenvironments. Overall survival was significantly decreased in the cohort of patients with PM co‐expressing CD70 and PD‐L1 (p < 0.0001). In vitro experiments revealed that PD‐L1 and CD70 additively enhanced the motility and invasiveness of PM cells. In contrast, PM cell proliferation was suppressed by PD‐L1. PD‐L1 enhanced mesenchymal phenotypes such as N‐cadherin up‐regulation. Collectively, these findings suggest that CD70 and PD‐L1 both enhance the malignant phenotypes of PM and diminish anti‐tumour immune responses. Based on our observations, combination therapy targeting these signalling pathways might be useful in patients with PM.