Oligomeric Cystatin C Supports the Immunosuppressive Activity of Myeloid Cells Through Interaction With Inhibitory Receptors

Authors

Chengcheng Zhang
Yubo He
Xiaoye Liu
Jingjing Xie
Meng Fang
Xing Yang
Ryan Huang
Qi Lou
Bufan Li
Ankit Gupta
Cheryl Lewis
Marc I Diamond
Ningyan Zhang
Zhiqiang An
Cheng Cheng Zhang

Language

English

Publication Date

11-14-2025

Journal

Signal Transduction and Targeted Therapy

DOI

10.1038/s41392-025-02462-x

PMID

41233352

PMCID

PMC12615798

PubMedCentral® Posted Date

11-14-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Amyloid proteins are linked to various diseases; however, their functional roles in immunity and cancer remain unclear. Here, we establish a direct link between oligomeric cystatin C-a cysteine cathepsin inhibitor and a well-characterized amyloidogenic protein-within the tumor microenvironment and the immune inhibitory receptors LILRB2 and LILRB5 on myeloid cells. We demonstrated that human LILRB2 and LILRB5, along with their murine counterpart PIRB, serve as functional receptors for cystatin C oligomers. Engagement of these inhibitory receptors by oligomeric cystatin C enhances the immunosuppressive activity of myeloid cells, leading to T-cell suppression and tumor progression. Deletion of the CST3 gene, which encodes cystatin C, in host mice and tumor cells impaired tumor growth, whereas its overexpression accelerated cancer progression in LILRB2 and LILRB5 transgenic mice. Mechanistically, cystatin C-LILRB2 signaling is driven by both canonical phosphatases and the enhanced TGF-β pathway. Additionally, we identified interactions between LILRB receptors and transthyretin oligomers, another amyloid linked to transthyretin amyloidosis, suggesting a broader paradigm of amyloid-LILRB interactions. Our findings reveal an unexpected role of oligomeric cystatin C in enhancing myeloid cell immunosuppression, expand the functional spectrum of amyloid proteins and underscore the importance of these proteins in immune evasion and cancer development.

Keywords

Animals, Humans, Cystatin C, Mice, Receptors, Immunologic, Myeloid Cells, Membrane Glycoproteins, Mice, Transgenic, Tumor Microenvironment, Signal Transduction, Tumour immunology, Tumour immunology

Published Open-Access

yes

Recommended Citation

Zhang, Chengcheng; He, Yubo; Liu, Xiaoye; et al., "Oligomeric Cystatin C Supports the Immunosuppressive Activity of Myeloid Cells Through Interaction With Inhibitory Receptors" (2025). Faculty, Staff and Student Publications. 5273.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5273