E-cadherin expression promotes tumor growth via KLRG1-dependent pathways

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.