PD-L1 Translocation to the Plasma Membrane Enables Tumor Immune Evasion Through MIB2 Ubiquitination

Authors

Xinfang Yu
Wei Li
Haidan Liu
Xu Wang
Cristian Coarfa
Chao Cheng
Xinlian Yu
Zhaoyang Zeng
Ya Cao
Ken H Young
Yong Li

Publication Date

2-1-2023

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI160456

PMID

36719382

PMCID

PMC9888393

PubMedCentral® Posted Date

2-1-2023

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Animals, Mice, B7-H1 Antigen, Cell Line, Tumor, Cell Membrane, Immune Evasion, Programmed Cell Death 1 Receptor, Tumor Escape, Ubiquitination, Cell Biology, Oncology, Cancer, Cancer immunotherapy, Cellular immune response

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 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.

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