PTEN Loss Increases PD-L1 Protein Expression and Affects the Correlation between PD-L1 Expression and Clinical Parameters in Colorectal Cancer

Abstract

BackgroundProgrammed death ligand-1 (PD-L1) has been identified as a factor associated with poor prognosis in a range of cancers, and was reported to be mainly induced by PTEN loss in gliomas. However, the clinical effect of PD-L1 and its regulation by PTEN has not yet been determined in colorectal cancer (CRC). In the present study, we verified the regulation of PTEN on PD-L1 and further determined the effect of PTEN on the correlation between PD-L1 expression and clinical parameters in CRC.Methods/ResultsRNA interference approach was used to down-regulate PTEN expression in SW480, SW620 and HCT116 cells. It was showed that PD-L1 protein, but not mRNA, was significantly increased in cells transfected with siRNA PTEN compared with the negative control. Moreover, the capacity of PTEN to regulate PD-L1 expression was not obviously affected by IFN-γ, the main inducer of PD-L1. Tissue microarray immunohistochemistry was used to detect PD-L1 and PTEN in 404 CRC patient samples. Overexpression of PD-L1 was significantly correlated with distant metastasis (P<0.001), TNM stage (P<0.01), metastatic progression (P<0.01) and PTEN expression (P<0.001). Univariate analysis revealed that patients with high PD-L1 expression had a poor overall survival (P<0.001). However, multivariate analysis did not support PD-L1 as an independent prognostic factor (P = 0.548). Univariate (P<0.001) and multivariate survival (P<0.001) analysis of 310 located CRC patients revealed that high level of PD-L1 expression was associated with increased risks of metastatic progression. Furthermore, the clinical effect of PD-L1 on CRC was not statistically significant in a subset of 39 patients with no PTEN expression (distant metastasis: P = 0.102; TNM stage: P = 0.634, overall survival: P = 0.482).ConclusionsPD-L1 can be used to identify CRC patients with high risk of metastasis and poor prognosis. This clinical manifestation may be partly associated with PTEN expression.

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“…High PD-L1 expression was associated with improved DFS and OS on both uni-and multivariate analysis. Our results are not in agreement with previous studies demonstrating an adverse prognostic effect of PD-L1 expression by IHC in several cancers including renal, colorectal, and lung cancers (23)(24)(25). Other studies in metastatic melanomas, non-small cell lung cancer, Merkel cell carcinomas, by using the validated antibody clone 5H1, they demonstrated a positive association of high PD-L1 expression and elevated TILs with longer survival (26)(27)(28).…”

PKB/Akt-dependent regulation of inflammation in cancer

“…1) [85]. Oncogenic activation of PKB increases the expression PD-L1 in gliomas, lung cancers and colon cancers in an mTOR-dependent fashion [85][86][87]. Conversely, selective inhibition of PKB with small molecules downregulates PD-L1 expression [85].…”

JNK signaling pathway is involved in piperlongumine-mediated apoptosis in human colorectal cancer HCT116 cells

“…The procedures for western blotting were performed as described previously (22). Briefly, equal amounts of protein were separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a polyvinylidene difluoride membrane (Millipore, Billerica, MA, USA).…”