Eph Receptors Activate Myeloid Checkpoint Receptor LILRB5 to Support Tumor Development

Authors

Yubo He
Chengcheng Zhang
Lingxiao Tan
Mi Deng
Xiaoye Liu
Ryan Huang
Xing Yang
Jingjing Xie
Qi Lou
Meng Fang
Caroline Smith
Samuel John
Wei Xiong
Xin Li
Cheryl Lewis
Jade Homsi
Ankit Gupta
Ningyan Zhang
Zhiqiang An
Cheng Cheng Zhang

Language

English

Publication Date

6-4-2025

Journal

Cancer Immunology Research

DOI

10.1158/2326-6066.CIR-24-0737

PMID

40145984

PMCID

PMC12137008

PubMedCentral® Posted Date

12-4-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid cells from patients with cancer in vitro. Upon myeloid cell-specific expression of LILRB5 in transgenic mice, the interaction between the Eph receptor on tumor cells and LILRB5 on myeloid cells led to increased tumor growth, increased immunosuppressive myeloid cells, and decreased frequencies of functional T cells compared with control mice. Eph-induced LILRB5 signaling and functions were reversed by LILRB5 blockade. In sum, certain Eph receptors functionally interact with the myeloid checkpoint receptor LILRB5 resulting in bidirectional signaling, and LILRB5 plays an important role in supporting immunosuppressive myeloid cells and sustaining tumor development.

Keywords

Animals, Receptors, Immunologic, Humans, Mice, Myeloid Cells, Neoplasms, Receptors, Eph Family, Signal Transduction, Mice, Transgenic, Mice, Inbred C57BL, Cell Line, Tumor

Published Open-Access

yes

Recommended Citation

He, Yubo; Zhang, Chengcheng; Tan, Lingxiao; et al., "Eph Receptors Activate Myeloid Checkpoint Receptor LILRB5 to Support Tumor Development" (2025). Faculty, Staff and Student Publications. 5272.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5272