Targeting the novel immune checkpoint KLRG1 is markedly therapeutic against cancer through multiple lymphocyte subsets.

BACKGROUND: Checkpoint blockade therapies have demonstrated clinical benefit across multiple cancer types; however, many patients with immune cell infiltration remain non-responsive or develop resistance. This suggests that additional, unidentified regulatory pathways limit treatment efficacy. The purpose of this study was to investigate the role of the inhibitory receptor KLRG1 in limiting antitumor immunity and to evaluate its potential as a therapeutic target in patients refractory to first-generation checkpoint inhibitors. METHODS: The study used murine models to observe KLRG1 expression following checkpoint therapy and analyzed tumor-infiltrating T cells from patients with melanoma non-responsive to anti-programmed death-1 (PD-1). We generated KLRG1 knockout mice and B16 melanoma N-cadherin (KLRG1 ligand) deletions to assess tumor growth. Additionally, a KLRG1 human knock-in mouse model and a novel anti-human KLRG1 monoclonal antibody (mAb) were developed and tested both in vitro and in vivo. RESULTS: KLRG1 was found to be upregulated on murine CD8+T cells post-therapy, and high KLRG1 expression correlated with anti-PD-1 resistance in patients with melanoma. KLRG1 knockout mice showed significantly reduced tumor growth, a response dependent on CD8(+) T cells, natural killer cells, and γδ T cells. Similarly, deleting N-cadherin in tumors slowed growth. The novel anti-human KLRG1 mAb enhanced human T-cell activation in vitro and significantly reduced tumor progression in humanized KLRG1 mice. CONCLUSIONS: Our findings demonstrate KLRG1 as a critical negative regulator of antitumor immunity and support KLRG1-cadherin blockade as a promising strategy for improving immunotherapy outcomes.