CMTM4 regulates epithelial–mesenchymal transition and PD‐L1 expression in head and neck squamous cell carcinoma

Abstract

The epithelial-mesenchymal transition (EMT) is a pivotal step involved in cancer recurrence and metastasis. In addition, the activation of the EMT program can induce a cancer stem cell (CSC)-like phenotype and programmed death-ligand 1 (PD-L1) expression in head and neck squamous cell carcinoma (HNSCC). The CMTM family has reported as an important regulator in this process. Here, we investigated the role of CMTM4 in HNSCC. We indicated that CMTM4 was overexpressed in human and mouse HNSCC samples and in HNSCC cell lines by immunohistochemistry and Western blot. A high expression level of CMTM4 was correlated with advanced lymph node metastasis and a negative prognosis. CMTM4-knockdown by small interfering RNA downregulated the EMT process and inhibited the migration and invasion abilities of tumor cells. Moreover, knockdown of CMTM4 decreased CSC-associated markers via the protein kinase B pathway.Notably, CMTM4-knockdown inhibited the expression of interferon-γ induced PD-L1 in HNSCC cells. A positive correlation was found between CMTM4 expression and CD8 + and PD-1 + cell density in the stroma. Our findings indicated that CMTM4 may play an important role in regulating EMT/CSC phenotypes and PD-L1 expression. This study may reinforce the interest in CMTM4 as a potential target for the prognosis and treatment of HNSCC.

Co-Expression with Membrane CMTM6/4 on Tumor Epithelium Enhances the Prediction Value of PD-L1 on Anti-PD-1/L1 Therapeutic Efficacy in Gastric Adenocarcinoma

“…CMTM6 interacts with PD-L1 in the plasma membrane and prevents PD-L1 from ubiquitin-mediated degradation. CMTM4 is closely related to CMTM6 and regulates PD-L1 expression in a similar way in head and neck squamous cell carcinoma and a CMTM6depleted lung cancer cell line [13][14][15]. These data suggest that CMTM6/4 could be new biomarkers for patients that undergo anti-PD-1/L1 immunotherapy.…”

Bidirectional crosstalk between epithelial-mesenchymal plasticity and IFNγ-induced PD-L1 expression promotes tumor progression

“…In this phase diagram, the IFNγ-induced leftward shift is clearly visible. Additionally, it shows that the total range of SNAIL1 for which the hybrid E/M phenotype, a particularly aggressive EMT phenotype (Lüönd et al, 2021, and reviewed in Jolly, Somarelli, et al, 2018), can (co-)exist is unaffected.…”

“…Even though partially conflicting findings between our model and published data can be reconciled, it is also likely that additional mechanisms by which PD-L1 and EMT mutually influence each other play a role depending on the studied cell line or cancer. For instance, PD-L1 expression can induce EMT by activating the TF SREBP-1c in hepatocellular and renal cell carcinoma (Wang et al, 2015;Xu et al, 2020), ZEB1 can bind and silence IRF1, a TF of PD-L1 (Jun Yang et al, 2017), and activity of the CMTM family, which stabilizes PD-L1, correlates with EMT-TFs such as SLUG (Jie Wu, 2020;Li et al, 2021).…”

“…We assumed µ 0 = 10 4 molecules to be the same as in Jolly, Tripathi, D. Jia, et al (2016). Transport of PD-L1 through various cellular compartments is modeled with a constant rate from compartment to compartment, with rates assumed to be similar to Lippincott-Schwartz, Roberts, and Hirschberg (2000). Model parameters are provided in Table 3; some parameters were considered to be similar to those of the simplified TCS model.…”

CMTM6 and CMTM4 as two novel regulators of PD-L1 modulate the tumor microenvironment

“…Furthermore, CMTM6 expression was positively correlated with PD-L1 expression in various cancers including HNSCC (18), lung cancer (30,69), gliomas (20), gastric cancer (33,36), and colon cancer (40) (Table 1). Similarly, CMTM4 was also identified as the positive regulator of PD-L1 in many tumors, such as in HCC (88) and in HNSCC (42). Mechanistically, CMTM6 could stabilize PD-L1 by preventing PD-L1 from lysosome-mediated degradation.…”