Claudins interact with LILRB immune inhibitory receptors to promote myeloid immunosuppression in cancer
Year: 2026
Type: article
Abstract: The mechanisms underlying tumor cell-myeloid cell interactions in the tumor microenvironment (TME) remain unclear, and predictive biomarkers for patient response to myeloid checkpoint blockade are lacking. This study identified specific binding between tight junction claudins (CLDNs) and leukocyte immunoglobulin-like receptor subfamily B2 (LILRB2) and LILRB5. In multiple human cancer cohorts, the spatial proximity of LILRB2-positive macrophages to CLDN-expressing cancer cells correlated with clinical outcomes, highlighting this spatial relationship as a potential biomarker. In syngeneic LILRB2-transgenic and humanized mouse models, CLDN18.2-LILRB2 interactions triggered bidirectional signaling, enhanced the immunosuppressive activity of myeloid cells, and accelerated tumor progression. These effects were reversed by LILRB2 blockade. The CLDN-LILRB2 axis sustained immunosuppression by regulating NF-κB and STAT signaling pathways. Our findings reveal a mechanism of myeloid cell regulation by tight junction proteins in the TME, offering a rationale for targeting this pathway in cancer therapy.
Source: Science Immunology
Authors: Xiaoye Liu, Ryan Huang, Zhiqiang Ku, Jingjing Xie, Heyu Chen, Yubo He, Qi Lou, Chengcheng Zhang, Chengcheng Zhang, Xing Yang, Cheryl Lewis, Jade Homsi, Ankit Gupta, Lei Dong, Kenian Chen, Annabel Tu, Liming Du, Hailong Yu, Qing Hu, Meng Fang, Bufan Li, A. E. M. Adan Khan, Caroline Simith, Samuel John, Lin Xu, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang, Cheng Cheng Zhang
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1241018968, Therapeutic Monoclonal Antibody Lead Optimization and Development Core, G2657489571, Targeting immunosuppressive myeloid cells in tumor microenvironment, G3762527287, Advanced Cancer Antibody Drug Modalities Core Facility, G5442619333, UT Southwestern Medical Center Simmons Comprehensive Cancer Center, Reprogramming myeloid cells to inhibit cancer development
OpenAlex ID: W7148671458