The let-7 family of microRNAs suppresses immune evasion in head and neck squamous cell carcinoma by promoting PD-L1 degradation

Abstract

Background: 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. However, cancer cellintrinsic 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). Methods: The 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 βcatenin/STT3 pathway was evaluated. Immune recognition of HNSCC in vivo was examined in subcutaneous tumorbearing C3H mice in the presence of let-7a/b and/or CTLA-4 antibody. Results: The 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 overexpression. 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. Conclusions: Taken together, our findings highlight targeting let-7 family as a potential strategy to enhance immune checkpoint therapy for HNSCC.

PD-L1 Expression Is Associated with Deficient Mismatch Repair and Poor Prognosis in Middle Eastern Colorectal Cancers

“…Several studies have shown that PD-1/PD-L1 pathway has become a potential therapeutic target for a wide range of human malignancies [28][29][30][31][32][33]. However, the associations between expression of PD-L1 and clinico-pathological parameters are not consistent [18,34,35].…”

Changes in Protein Glycosylation in Head and Neck Squamous Cell Carcinoma

“…Let-7a/b can inhibit PD-L1 glycosylation and promote PD-L1 degradation in HNSCC, and the process is achieved via the β-catenin/STT3 pathway 103 . EMT can induce the N-glycosyltransferase STT3 through β-catenin transcription, stabilize the N-glycosylation of PD-L1 and increase its expression, finally helping CSCs escape from the immune system 104 .…”

miRNA-Based Therapeutics in the Era of Immune-Checkpoint Inhibitors

“…The combination led to the most profound reduction in tumor mass. Analysis of the tumor samples revealed that the combination led to marked CD8+ T cell infiltration and profound IFN-γ production in tumor-infiltrating lymphocytes indicating enhanced immune activity and a potential synergism [ 97 ]. These results indicate that the let-7 family of miRNAs has potent activity in the microenvironment by shifting immune cells towards an antitumor phenotype often required for successful ICI treatment.…”