Science Immunology | CLDN18.2-LILRB2 Interaction Promotes Myeloid Immune Suppression and Drives Tumor Progression

This study reveals that tumor cells directly interact with LILRB2 on myeloid cells via CLDN18.2, reshaping the immune microenvironment. It provides a novel strategy for designing combination therapies targeting myeloid checkpoints, offering important insights for intervention in 'cold tumors'.

 

Literature Overview

The article titled 'Claudins interact with LILRB immune inhibitory receptors to promote myeloid immunosuppression in cancer,' published in Science Immunology, systematically investigates the transcellular interaction mechanism between the tight junction protein CLDN18.2 and the immune inhibitory receptor LILRB2 in the tumor microenvironment. The study finds that this axis strengthens the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) through bidirectional signaling, while also inhibiting T cell activity, thereby promoting tumor immune escape. Spatial transcriptomic analysis across multiple patient cohorts confirms that spatial proximity between LILRB2^hi macrophages and CLDN18.2⁺ tumor cells predicts poor prognosis, highlighting its potential value as a biomarker.

Background Knowledge

Currently, in epithelial tumors such as gastric and pancreatic cancers, CLDN18.2 has been established as a therapeutic target—for example, through the use of monoclonal antibodies like zolbetuximab—yet its role in immune regulation has long been overlooked. Myeloid cells are highly enriched in the tumor microenvironment and are key mediators in establishing an immunosuppressive TME, although the signaling networks driving their functional polarization remain incompletely understood. Existing immune checkpoint therapies primarily focus on T cell exhaustion, while interventions targeting myeloid checkpoints are still in early stages. Although LILRB2 is a well-known immune inhibitory receptor that binds ligands such as MHC-I, its interaction with tumor cell ligands in solid tumors has been largely unexplored. This study systematically screened transmembrane protein interaction networks and, for the first time, identified CLDN family members as high-affinity ligands for LILRB2 and LILRB5, challenging the long-held view that tight junction proteins are solely involved in barrier functions and providing a new dimension for understanding tumor-immune interactions.

 

 

Research Methods and Experiments

The authors employed high-throughput membrane protein interaction screening combined with an LILRB2 chimeric receptor reporter system to systematically validate the specific binding between CLDN18.2 and LILRB2, confirming their direct interaction through surface plasmon resonance and co-immunoprecipitation. Using point mutations and domain deletion experiments, they identified the GLW motif within the ECL1 domain of CLDN18.2 as the critical binding site for LILRB2, with the D1–D3 domains of LILRB2 mediating this interaction. To investigate its biological function, the study generated myeloid-specific LILRB2 transgenic mice (LILRB2-Tg; LysM-Cre) to mimic human receptor function in an immunocompetent setting. By transplanting MC38 tumor cells expressing CLDN18.2, they confirmed that this axis significantly promotes tumor growth and metastasis. Additionally, using a humanized mouse model (NSG-SGM3 + human CD34⁺ cells), they validated the conservation of the CLDN18.2–LILRB2 interaction in the human immune system and its role in reprogramming myeloid cell functions.

Key Conclusions and Perspectives

• CLDN18.2 directly binds LILRB2 via its ECL1 domain, activating downstream SHP-1/2 signaling, suppressing the NF-κB pathway, and activating STAT1/3, thereby upregulating PD-L1 and IDO1 expression and enhancing the immunosuppressive function of MDSCs. This finding suggests that CLDN18.2 is not only a tumor antigen but also an immune regulatory ligand, and future therapies targeting this axis could synergize with anti–PD-1 treatments.
• Spatial transcriptomic analysis reveals that the proximity of LILRB2^hi macrophages to CLDN18.2⁺ tumor cells is significantly associated with poor patient prognosis, suggesting this spatial axis could serve as a potential biomarker for 'cold tumors' and guide patient selection for LILRB2-targeted therapies.
• Blocking antibodies against LILRB2 reverse the immunosuppressive phenotype induced by CLDN18.2, restore T cell activity, and exhibit synergistic antitumor effects when combined with anti–PD-L1 therapy. This provides a solid foundation for the clinical development of LILRB2 monoclonal or bispecific antibodies, particularly for tumors with high CLDN18.2 expression.
• The CLDN18.2–LILRB2 interaction triggers bidirectional signaling: in addition to activating myeloid cells, it also promotes tumor cell proliferation via the ERK/AKT pathway. This reveals a novel mechanism of cross-lineage signaling in the tumor microenvironment, suggesting that targeting this interaction could simultaneously inhibit both autonomous and non-autonomous tumor growth.

Research Significance and Prospects

This study fundamentally expands our understanding of CLDN protein functions, redefining them from structural proteins to immune regulatory ligands, and provides a novel target for developing new immune checkpoint inhibitors. From a drug development perspective, biologics targeting LILRB2 or blocking the CLDN18.2–LILRB2 interaction—such as monoclonal or bispecific antibodies—could become valuable additions to current immunotherapies, especially for 'cold tumors' with insufficient T cell infiltration. In clinical monitoring, spatial proximity metrics could serve as potential biomarkers for patient stratification, improving the accuracy of treatment response prediction. Furthermore, this mechanism may not be limited to CLDN18.2; other CLDN family members might similarly regulate immunity under specific pathological conditions, warranting further investigation.

 

 

Conclusion

This study uncovers a novel mechanism by which tumor cells establish an immunosuppressive microenvironment through direct interaction between CLDN18.2 and myeloid cell LILRB2. This finding not only explains potential reasons for heterogeneous responses to CLDN18.2-targeted therapies but also proposes a new combinatorial therapeutic strategy targeting both CLDN18.2 and LILRB2. From bench to bedside, this axis provides a targetable immune escape pathway for 'cold tumors,' potentially enhancing antitumor immune responses by restoring the immunostimulatory potential of myeloid cells. In the future, biomarker development and clinical translation based on this mechanism will bring more precise immunotherapies to patients with CLDN18.2-high tumors such as gastric and pancreatic cancers, positioning this pathway as a pivotal node in reshaping the tumor immune microenvironment.

 

Xiaoye Liu, Ryan Huang, Zhiqiang Ku, Zhiqiang An, and Cheng Cheng Zhang. Claudins interact with LILRB immune inhibitory receptors to promote myeloid immunosuppression in cancer. Science immunology.