Strategic Targeting of CENPE-PDL1 axis in NSCLC

Abstract Background Increasing evidence suggests that centromere-associated protein E (CENP-E) is expressed during mitosis and plays a key role in incorrect chromosome alignment. Therefore, CENP-E may represent a druggable target for several solid tumors. Methods Here, we evaluated the ability of the CENPE inhibitor GSK923295 to up-regulate PDL1 and induce immune responses to tumor-associated CD8 T cell and regulatory T (Treg) cell.Results Our study found that a CENP-E inhibitor exhibited anti-tumor activity by directly suppressing the proliferation of lung cancer cells and upregulating the expression of PD-L1. Inhibition of CENP-E suppressed antitumor immunity by attenuating the response of activated CD8+ T cells and augmenting Tregs in vitro and in vivo. Mechanistically, CENP-E bound to the TTP promoter to regulate its transcription, and inhibition of CENP-E stabilized the mRNA of PD-L1 via TTP targeting of the 3’UTR. Inhibition or knockdown of CENP-E combined with an anti-PD-L1 antibody rescued the impaired antitumor CD8+ T/Treg cell response and improved the antitumor effect in lung cancer. Surprisingly , further analysis found that CENP-E was only related to the poor prognosis of lung cancer. Conclusions All of these results suggest that a CENP-E inhibitor will exert anti-tumor effects and upregulate PD-L1-induced impairment of anti-tumor CD8+/Treg cell responses in lung cancer. However, elevated PDL1 levels provide a possible strategy for combination immunotherapy, and this combination of immunotherapeutic strategies may offset the negative effects of a CENP-E inhibitor on its immune-mediated antitumor ability in lung cancer treatment.