Loss of VGLL 4 suppresses tumor PD ‐L1 expression and immune evasion

Abstract

Targeting immune checkpoints, such as PD‐L1 and its receptor PD‐1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD‐L1 and PD‐1 will improve the clinical response rate and efficacy of PD‐1/PD‐L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP‐induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti‐tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell‐mediated tumor regression in murine syngeneic models. VGLL4 deficiency reduces PD‐L1 expression in tumor cells. VGLL4 interacts with IRF2BP2 and promotes its protein stability through inhibiting proteasome‐mediated protein degradation. Loss of IRF2BP2 results in persistent binding of IRF2, a transcriptional repressor, to PD‐L1 promoter. In addition, YAP inhibits IFNγ‐inducible PD‐L1 expression partially through suppressing the expression of VGLL4 and IRF1 by YAP target gene miR‐130a. Our study identifies VGLL4 as an important regulator of PD‐L1 expression and highlights a central role of VGLL4 and YAP in the regulation of tumor immunity.

IRF2BP2: A new player in the regulation of cell homeostasis

“…This study confirmed the finding of Teng and colleagues showing that VGLL4 interacts with and further showed that VGLL4 protects IRF2BP2 from ubiquitination, decreasing K48‐linked polyubiquitination. Consequently, VGLL4 protects IRF2BP2 from the proteasome‐dependent degradation pathway and stabilizes the protein . As another posttranslational regulation, IRF2BP2 can be strongly phosphorylated.…”

“…Thus, the authors suggested that IFN‐γ stimulation triggers the release of IRF‐2 from the PD‐L1 promoter and regulates the dynamic association between IRF‐2 and IRF2BP2, favoring PD‐L1 expression. Whether this interaction is regulated by posttranslational modification needs to be clarified …”

“…IRF2BP2 acts as a positive and negative regulator of gene expression by playing a role in different cellular functions, such as apoptosis, survival, and cell differentiation . Some studies have suggested that IRF2BP2 is involved in angiogenesis during cancer development, DNA repair, gene fusion, and immune system evasion . Furthermore, it has been recently reported that IRF2BP2 has a role in macrophage regulation and lymphocyte activation, highlighting its function in the innate and adaptive immune responses.…”

Down‐regulation of interferon regulatory factor 2 binding protein 2 suppresses gastric cancer progression by negatively regulating connective tissue growth factor

“…A previous study indicates that VGLL4 binds to IRF2BP2 to promote PD‐L1 expression and induces immune evasion through IRF2 inhibition in lung cancer . The binding of VGLL4 to IRF2BP2 also activates the expression of VEGF‐A in muscle cells .…”

“…21,22 A previous study indicates that VGLL4 binds to IRF2BP2 to promote PD-L1 expression and induces immune evasion through IRF2 inhibition in lung cancer. 23 The binding of VGLL4 to IRF2BP2 also activates the expression of VEGF-A in muscle cells. 24 This evidence implies that IRF2BP2 may cross talk with Hippo pathway and CTGF via binding to VGLL4.…”