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

Transformed cells frequently adapt to immune pressure by modulating expression of ligands for PD-1 and CTLA-4. Despite the success of therapies targeting these interactions, only a minority of patients experience a clinical response, highlighting the critical need for alternative targets. Prior work from our group showed that the inhibitory receptor KLRG1 binds to tumor-derived E-cadherin. However, the therapeutic potential of targeting KLRG1 signaling remains incompletely understood. To address this, we generated a library of cancer cell lines engineered to express varying levels of E-cadherin. Across multiple models, we demonstrate that E-cadherin expression renders tumors more aggressive in vivo. Using an RMA-S cell line possessing a mutated E-cadherin that abrogates KLRG1 binding while preserving cadherin homotypic interactions, we demonstrate that the protumor effect of E-cadherin expression is largely mediated by KLRG1. To further dissect the cellular targets of KLRG1 signaling, we generated KLRG1fl/fl mice and performed lineage-specific deletion. Surprisingly, we discovered that KLRG1 expression on CD8+ T cells, rather than on natural killer cells, impairs the immune control of B16-F10 E-cadherin+ tumors. Taken together, these results reveal an underappreciated protumor role for E-cadherin and highlight KLRG1 as a promising target for future checkpoint blockade strategies, particularly in tumors retaining epithelial features.