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PD-L1 ubiquitination by MIB2 enables its translocation to the plasma membrane for tumor immune evasion

ABSTRACT: Programmed death-ligand 1 (PD-L1), a critical immune checkpoint ligand, is a transmembrane protein synthesized in the endoplasmic reticulum of tumor cells and transported to the plasma membrane to interact with programmed death 1 (PD-1) expressed on T cell surface. This interaction delivers co-inhibitory signals to T cells, thereby suppressing their function and evading antitumor immunity. Most companion or complementary diagnostic devices for PD-L1 expression levels in tumor cells used in the clinic or clinical trials require membranous staining. However, the mechanism driving PD-L1 translocation to the plasma membrane after de novo synthesis is poorly understood. Herein, we showed that mind bomb homolog 2 (MIB2) is required for PD-L1 transportation from the trans-Golgi network (TGN) to the plasma membrane of cancer cells. MIB2 deficiency leaded to fewer PD-L1 proteins on the tumor cell surface and promotes antitumor immunity in mice.We performed a single-cell RNA sequencing (scRNA-seq) of B16-F10 tumors from C57BL/6 syngeneic mice. Knockdown of MIB2 resulted in an increase in the percentage of CD8+ CTLs (approximately 5-fold) and CD4+/CD8+ effector/activated T cells (approximately 2-fold), indicating that MIB2 downregulation enhanced the antitumor immune activity centered on CD8+ CTLs and changed their transcriptional profile. Our findings demonstrate that non-proteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cells' immune evasion.

ORGANISM(S): Mus musculus

PROVIDER: GSE218906 | GEO | 2023/12/31

REPOSITORIES: GEO

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