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E-cadherin expression promotes tumor growth via KLRG1-dependent pathways
Jacob A Myers1, Alexander R D Jordon1, Samantha M Borys1
1Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, United States.
Journal of Immunology (Baltimore, Md. : 1950)
|April 24, 2026
Summary
Tumor cells expressing E-cadherin become more aggressive by engaging the KLRG1 receptor on CD8+ T cells, hindering immune control. Targeting KLRG1 offers a new strategy for cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Immune checkpoint inhibitors targeting PD-1 and CTLA-4 show limited efficacy in many patients.
- The inhibitory receptor KLRG1 (killer cell lectin-like receptor G1) binds to E-cadherin on tumor cells.
- The precise role of KLRG1 signaling in tumor progression and immune evasion is not fully understood.
Purpose of the Study:
- To investigate the therapeutic potential of targeting KLRG1 signaling in cancer.
- To determine the role of E-cadherin expression in tumor aggressiveness and immune evasion.
- To identify the specific immune cell populations mediating KLRG1's protumor effects.
Main Methods:
- Generated cancer cell lines with varying E-cadherin expression levels.
- Utilized an RMA-S cell line with mutated E-cadherin to abrogate KLRG1 binding.
- Created KLRG1fl/fl mice for lineage-specific deletion studies.
- Assessed tumor aggressiveness in vivo and immune cell function.
Main Results:
- E-cadherin expression increased tumor aggressiveness across multiple models.
- The protumor effect of E-cadherin was largely dependent on KLRG1 binding.
- KLRG1 expression on CD8+ T cells, not NK cells, impaired immune control of E-cadherin+ tumors.
- Identified KLRG1 as a key mediator of E-cadherin's protumorigenic function.
Conclusions:
- E-cadherin plays an underappreciated protumor role by engaging KLRG1 on CD8+ T cells.
- KLRG1 signaling on CD8+ T cells promotes tumor immune evasion.
- KLRG1 represents a promising novel target for cancer immunotherapy, especially in epithelial tumors.
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