@article{88b74d46ca294c079f0a50e9675940dc,
title = "Targeting glycosylated PD-1 induces potent antitumor immunity",
abstract = "Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using mAbs, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The mAb STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing antitumor immunity. Together, these findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy.",
author = "Linlin Sun and Chia-Wei Li and Chung, {Ezra M.} and Riyao Yang and Kim, {Yong Soo} and Park, {Andrew H.} and Lai, {Yun Ju} and Yi Yang and Wang, {Yu Han} and Jielin Liu and Yufan Qiu and Khoo, {Kay Hooi} and Jun Yao and Hsu, {Jennifer L.} and Jong-Ho Cha and Chan, {Li Chuan} and Jung-Mao Hsu and Heng-Huan Lee and Yoo, {Stephen S.} and Mien-Chie Hung",
note = "Funding Information: S.S. Yoo is a CEO and has ownership interest (including patents) in STCube Pharmaceiticals, Inc. M.-C. Hung reports receiving a commercial research grant and Funding Information: We would like to thank the Department of Scientific Publications at MD Anderson for editorial assistance. This work was funded in part by the following: National Natural Science Foundation of China (81972186 and 31301160 to L. Sun) and China Scholarship Council (to L. Sun); Natural Science Foundation of Tianjin (16JCYBJC24400 to L. Sun); Cancer Prevention & Research Institute of Texas (MIRA grant RP160710 to M.-C. Hung); National Breast Cancer Foundation, Inc.; Breast Cancer Research Foundation (BCRF-17-069 to M.-C. Hung); Patel Memorial Breast Cancer Endowment Fund (to M.-C. Hung); The University of Texas MD Anderson-China Medical University and Hospital Sister Institution Fund (to M.-C. Hung); U.S. National Institutes of Health Cancer Center Support Grant (CCSG CA016672 to M.-C. Hung) and T32 Training Grant (5T32CA186892 to H.-H. Lee and L.-C. Chan); YingTsai Young Scholar Award (CMU108-YTY-02 to J.-M. Hsu); Ministry of Education (Taiwan) Joint of International Talent Training Program (1040082029B to Y.-H. Wang); China Scholarship Council (to Y. Qiu); Ministry of Science and Technology (MOST 109-2314-B-001-002 to C.-W. Li); and The University of Texas MD Anderson Cancer Center Odyssey Fellowship Program (to Y. Yang). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = jun,
doi = "10.1158/0008-5472.CAN-19-3133",
language = "English (US)",
volume = "80",
pages = "2298--2310",
journal = "Cancer Research",
issn = "0008-5472",
number = "11",
}