ZG16 promotes T-cell mediated immunity through direct binding to PD-L1 in colon cancer

Hui Meng; Wu Yao; Yuhui Yin; Yizhen Li; Yi Ding; Liang Wang; Mingzhi Zhang

doi:10.1186/s40364-022-00396-y

ZG16 promotes T-cell mediated immunity through direct binding to PD-L1 in colon cancer

Biomark Res. 2022 Jul 13;10(1):47. doi: 10.1186/s40364-022-00396-y.

Authors

Hui Meng^#¹, Wu Yao², Yuhui Yin³, Yizhen Li³, Yi Ding³, Liang Wang⁴, Mingzhi Zhang^#⁵

Affiliations

¹ Department of Pathology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. menghui2000@zzu.edu.cn.
² College of Public Health, Zhengzhou University, Zhengzhou, Henan, China.
³ Department of Pathology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
⁴ Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁵ Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. mingzhi_zhang@126.com.

^# Contributed equally.

Abstract

Immunotherapy using programmed cell death 1 (PD1) inhibitors has shown great efficacy in colorectal cancer patients harboring mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) alterations. We previously showed a negative correlation of zymogen granule protein 16 (ZG16) with programmed death-ligand 1 (PD-L1) expression in patients with colorectal cancer. However, how ZG16 regulates PD-L1 expression is unclear. In this study, we showed that ZG16 can directly bind to glycosylated PD-L1 through its lectin domain, leading to PD-L1 degradation. Mutations on the lectin domain of ZG16 largely inhibit the interaction between ZG16 and PD-L1. Importantly, ZG16 overexpression suppressed tumor growth in two syngeneic mouse models through blockage of PD-L1 expression in cancer cells meanwhile suppression of PD1 expression in T cells. We also showed that ZG16 could improve the effect of chemotherapy and may be delivered as a protein to serve as an immune checkpoint inhibitor to promote T-cell mediated immunity.

Keywords: Colorectal cancer; PD-L1; PD1; T cells; ZG16.

Publication types

Letter