Although
immunotherapy (anti-PD-1/PD-L1
antibodies) has been approved for clinical treatment of
lung cancer, only a small proportion of patients respond to monotherapy. Hence, understanding the regulatory mechanism of PD-L1 is particularly important to identify optimal combinations. In this study, we found that inhibition of CDK5 induced by
shRNA or CDK5 inhibitor leads to reduced expression of
PD-L1 protein in human
lung adenocarcinoma cells, while the
mRNA level is not substantially altered. The
PD-L1 protein degradation is mediated by
E3 ligase TRIM21 via ubiquitination-
proteasome pathway. Subsequently, we studied the function of CDK5/PD-L1 axis in LUAD. In vitro, the absence of CDK5 in mouse Lewis
lung cancer cell (LLC) has no effect on cell proliferation. However, the attenuation of CDK5 or combined with anti-PD-L1 greatly suppresses
tumor growth in LLC implanted mouse models in vivo. Disruption of CDK5 elicits a higher level of CD3+, CD4+ and CD8+ T cells in spleens and lower PD-1 expression in CD4+ and CD8+ T cells. Our findings highlight a role for CDK5 in promoting antitumor immunity, which provide a potential therapeutic target for combined
immunotherapy in LUAD.