RT Journal Article
SR Electronic
T1 THADA drives Golgi residency and upregulation of PD-L1 in cancer cells and provides promising target for immunotherapy
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP e002443
DO 10.1136/jitc-2021-002443
VO 9
IS 8
A1 Li, Chushu
A1 Chi, Hao
A1 Deng, Shouyan
A1 Xu, Ke
A1 Wang, Huanbin
A1 Yao, Han
A1 Wang, Yungang
A1 Chen, Dawei
A1 Guo, Xun
A1 Fang, Jing-Yuan
A1 He, Fang
A1 Xu, Jie
YR 2021
UL http://jitc.bmj.com/content/9/8/e002443.abstract
AB Background The abnormal upregulation of programmed death-ligand 1 (PD-L1) in cancer cells inhibits T cell-mediated cytotoxicity, but the molecular mechanisms that drive and maintain PD-L1 expression are still incompletely understood.Methods Combined analyses of genomes and proteomics were applied to find potential regulators of PD-L1. In vitro experiments were performed to investigate the regulatory mechanism of PD-L1 by thyroid adenoma associated gene (THADA) using human colorectal cancer (CRC) cells. The prevalence of THADA was analyzed using CRC tissue microarrays by immunohistochemistry. T cell killing assay, programmed cell death 1 binding assay and MC38 transplanted tumor models in C57BL/6 mice were developed to investigate the antitumor effect of THADA.Results THADA is critically required for the Golgi residency of PD-L1, and this non-redundant, coat protein complex II (COPII)-associated mechanism maintains PD-L1 expression in tumor cells. THADA mediated the interaction between PD-L1 as a cargo protein with SEC24A, a module on the COPII trafficking vesicle. Silencing THADA caused absence and endoplasmic reticulum (ER) retention of PD-L1 but not major histocompatibility complex-I, inducing PD-L1 clearance through ER-associated degradation. Targeting THADA substantially enhanced T cell-mediated cytotoxicity, and increased CD8+ T cells infiltration in mouse tumor tissues. Analysis on clinical tissue samples supported a potential role of THADA in upregulating PD-L1 expression in cancer.Conclusions Our data reveal a crucial cellular process for PD-L1 maturation and maintenance in tumor cells, and highlight THADA as a promising target for overcoming PD-L1-dependent immune evasion.Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. The authors declare that all data supporting the findings of this study are available within the paper and its supplementary information files.