Abstract
BackgroundAccumulation of immunosuppressive protein programmed death-ligand 1 (PD-L1) has been documented in several cancers and contributes to the evasion of the host immune system. However, cancer cell-intrinsic signaling-dependent control of PD-L1 expression remains to be elucidated. Herein, we aimed to identify the let-7 family of microRNAs as candidates that up-regulate tumor cell PD-L1 expression and mediates immune evasion of head and neck squamous cell carcinoma (HNSCC).MethodsThe expression of let-7 family and PD-L1 was quantified in HNSCC tissues and adjacent normal tissues. PD-L1 degradation was evaluated in HNSCC cells in response to elevated expressions of let-7a or let-7b. The regulation of let-7 family on PD-L1 degradation through a mechanism involving T-cell factor-4 (TCF-4) control of β-catenin/STT3 pathway was evaluated. Immune recognition of HNSCC in vivo was examined in subcutaneous tumor-bearing C3H mice in the presence of let-7a/b and/or CTLA-4 antibody.ResultsThe let-7 family were significantly down-regulated in the context of HNSCC, sharing a negative correlation with PD-L1 expression. Glycosylated PD-L1 was detected in HNSCC cells, which was reduced by let-7a/b over-expression. TCF-4, the target of let-7a/b, activated the β-catenin/STT3 pathway and promoted PD-L1 degradation. In vivo analysis demonstrated that let-7a/b over-expression potentiated anticancer immunotherapy by CTLA-4 blockade.ConclusionsTaken together, our findings highlight targeting let-7 family as a potential strategy to enhance immune checkpoint therapy for HNSCC.
Highlights
Accumulation of immunosuppressive protein programmed death-ligand 1 (PD-L1) has been documented in several cancers and contributes to the evasion of the host immune system
Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was applied to examine the expression of let-7 family of miRNAs in both the head and neck squamous cell carcinoma (HNSCC) tissues and adjacent normal tissues, the results of which revealed that the let-7 family of miRNAs was poorly expressed in HNSCC tissues (Fig. 1a; p < 0.05), indicating that down-regulated let-7 family of miRNAs could induce the development of HNSCC
Immunohistochemistry was employed in order to examine the expression of PD-L1 in HNSCC tissues and adjacent normal tissues, with the results revealing that HNSCC tissues presented with higher expression of PD-L1 compared to adjacent normal tissues (Fig. 1c; p < 0.05)
Summary
Accumulation of immunosuppressive protein programmed death-ligand 1 (PD-L1) has been documented in several cancers and contributes to the evasion of the host immune system. We aimed to identify the let-7 family of microRNAs as candidates that up-regulate tumor cell PD-L1 expression and mediates immune evasion of head and neck squamous cell carcinoma (HNSCC). Accumulation of PD-L1 mediated by STT3 on cancer stem cells has been hypothesized to potentially improve immune evasion in cancers [16], with the Wnt/β-catenin pathway earmarked as a crucial factor in the development of HNSCC [17]. Based on the aforementioned exploration of literature and question to be explored, we subsequently proposed the hypothesis that the let-7 family of miRNAs influences the immune evasion of HNSCC by regulating TCF-4 and PD-L1 via the β-Catenin/STT3 pathway, with the objective of verifying this hypothesis through a series of experiments and providing enhanced clinical insight for treating HNSCC
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