KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC

Immunotherapy has become a prominent first-line cancer treatment strategy.

In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy.

However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer.

In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation.

We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo.

These results indicate the important role of KEAP1 in anti-cancer immunity.

Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation.

Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis.

In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling.

Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC.