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


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 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.


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 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.


CONCLUSIONS
Taken together, our findings highlight targeting let-7 family as a potential strategy to enhance immune checkpoint therapy for HNSCC.
['Yu|Dan|D|', 'Liu|Xueshibojie|X|', 'Han|Guanghong|G|', 'Liu|Yan|Y|', 'Zhao|Xue|X|', 'Wang|Di|D|', 'Bian|Xiaomin|X|', 'Gu|Tingting|T|', 'Wen|Lianji|L|']
D060890:B7-H1 Antigen D002478:Cells, Cultured D006031:Glycosylation D057809:HEK293 Cells D006258:Head and Neck Neoplasms D006801:Humans D035683:MicroRNAs D059748:Proteolysis D015398:Signal Transduction D000077195:Squamous Cell Carcinoma of Head and Neck
Let-7 family Immune evasion Head and neck squamous cell carcinoma Programmed death-ligand 1 TCF-4 Glycosylation