2023 World Conference on Lung Cancer (Posters)-P1.04. CDK4/6 Inhibitor Improves Radioimmunotherapy Efficacy via Inducing PD-L1 Transcription through Increased c-Jun Activation in NSCLC

P1.04. CDK4/6 Inhibitor Improves Radioimmunotherapy Efficacy via Inducing PD-L1 Transcription through Increased c-Jun Activation in NSCLC - PDF(Abstract)

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This study explores the combined efficacy and underlying mechanisms of CDK4/6 inhibition combined with radioimmunotherapy in non-small cell lung cancer (NSCLC). Clinical trials have shown that the CDK4/6 inhibitor abemaciclib improves progression-free survival and objective response rate in NSCLC patients. It is also found to have synergistic anti-tumor effects with radiotherapy or PD-1 antibodies. <br /><br />In this study, a cell line-derived tumor xenograft mouse model is used to examine the combined effects of CDK4/6 inhibition and radioimmunotherapy on NSCLC growth in vivo. The results show that abemaciclib significantly enhances the combined effects of irradiation and anti-PD-1 antibodies on NSCLC growth, accompanied by increased infiltration of CD8 T cells and decreased regulatory T cells and myeloid-derived suppressor cells. <br /><br />The study also investigates the underlying mechanisms of this synergistic effect. It is found that abemaciclib induces PD-L1 transcription via activating the JNK/c-Jun pathway. The knockdown of c-Jun reverses this induction, indicating its role in regulating PD-L1 transcription. Moreover, c-Jun regulates PD-L1 transcription by targeting its promoter sequences, and its phosphorylation at Ser63 is found to be related to this process. <br /><br />The study concludes that CDK4/6 inhibition blocks its phosphorylation by JNK, which enhances the competitive phosphorylation of c-Jun in NSCLC cells. The activated c-Jun then boosts PD-L1 transcription. CDK4/6 inhibition also enhances the anti-tumor effects of irradiation and PD-1 antibody treatment by increasing CD8 T cell infiltration. The findings suggest that CDK4/6 inhibition could be a potential strategy to improve the efficacy of radioimmunotherapy in NSCLC.

Asset Subtitle

Yan Gong

Meta Tag

Speaker Yan Gong

Topic Tumor Biology: Preclinical Biology - Radiobiology

Keywords

CDK4/6 inhibition

radioimmunotherapy

NSCLC

abemaciclib

progression-free survival

synergistic effects

CD8 T cells

PD-L1 transcription

JNK/c-Jun pathway

anti-tumor effects