PD-L1 translocation to the plasma membrane enables tumor immune evasion through MIB2 ubiquitination

• Published in: The Journal of clinical investigation 2023-02, Vol.133 (3), p.1-15
• Main Authors: Yu, Xinfang, Li, Wei, Liu, Haidan, Wang, Xu, Coarfa, Cristian, Cheng, Chao, Yu, Xinlian, Zeng, Zhaoyang, Cao, Ya, Young, Ken H, Li, Yong
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; B cells; B7-H1 Antigen; Biological transport; Biomedical research; Cancer; Cell biology; Cell Line, Tumor; Cell Membrane - metabolism; Cell membranes; Cell surface; Cells; Clinical trials; Development and progression; Endoplasmic reticulum; Exocytosis; Genetic aspects; Golgi apparatus; Health aspects; Immune checkpoint; Immune Evasion; Ligands; Lymphocytes; Lymphocytes T; Membrane proteins; Metastasis; Mice; Oncology; Oncology, Experimental; PD-1 protein; PD-L1 protein; Physiological aspects; Plasma; Programmed Cell Death 1 Receptor - metabolism; Proteins; T cells; Tumor cells; Tumor Escape; Tumors; Ubiquitin; Ubiquitin-proteasome system; Ubiquitination
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI160456

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 coinhibitory signals to T cells, thereby suppressing their function and allowing evasion of antitumor immunity. Most companion or complementary diagnostic devices for assessing PD-L1 expression levels in tumor cells used in the clinic or in 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 led to fewer PD-L1 proteins on the tumor cell surface and promoted antitumor immunity in mice. Mechanistically, MIB2 catalyzed nonproteolytic K63-linked ubiquitination of PD-L1, facilitating PD-L1 trafficking through Ras-associated binding 8-mediated (RAB8-mediated) exocytosis from the TGN to the plasma membrane, where it bound PD-1 extrinsically to prevent tumor cell killing by T cells. Our findings demonstrate that nonproteolytic ubiquitination of PD-L1 by MIB2 is required for its transportation to the plasma membrane and tumor cell immune evasion.