PT - JOURNAL ARTICLE AU - Jiaxin Liu AU - Lingyun Wei AU - Nan Hu AU - Dong Wang AU - Juan Ni AU - Sha Zhang AU - Hongbing Liu AU - Tangfeng Lv AU - Jie Yin AU - Mingxiang Ye AU - Yong Song TI - FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer AID - 10.1136/jitc-2022-005116 DP - 2022 Sep 01 TA - Journal for ImmunoTherapy of Cancer PG - e005116 VI - 10 IP - 9 4099 - http://jitc.bmj.com/content/10/9/e005116.short 4100 - http://jitc.bmj.com/content/10/9/e005116.full SO - J Immunother Cancer2022 Sep 01; 10 AB - Background Activation of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been extensively described as a pivotal mechanism to escape immune surveillance and elicits suppressive effect on antitumor immunity. Blockade of the PD-1/PD-L1 interaction by checkpoint inhibitors has been shown to result in tumor shrinkage and prolong patient survival. However, regulatory machinery for PD-1/PD-L1 expression is largely unknown.Methods We used bioinformatic tools and biochemical methods to investigate the significance of F-box and WD repeat domain containing 7 (FBW7) in regulating PD-1 protein stability. By generating a panel of FBW7 and PD-1 encoding plasmids, we expressed FBW7 and PD-1 or their mutants to performed immunoprecipitation and immunoblotting assays. The efficacy of cotargeting FBW7 to enhance antitumor immunity was evaluated in C57BL/6J mice. These laboratory findings were further validated in tumor samples obtained from patients with non-small cell lung cancer (NSCLC).Results We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. Cotargeting FBW7 accelerates PD-1 protein degradation and enhances antitumor immunity in vivo. Moreover, we demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7. Higher expression of FBW7 characterizes a ‘hot’ tumor microenvironment and confers more favorable responses to PD-1 blockade therapy.Conclusions This study highlights the critical role of FBW7 in determining PD-1 protein stability. FBW7 ubiquitinates PD-1 in a phosphorylation-dependent manner, as a consequence, leading to PD-1 protein degradation and cytotoxic lymphocytes infiltrating the tumor microenvironment. Screening FBW7 status would predict clinical response to anti-PD-1 immunotherapy in patients with NSCLC, and targeting FBW7 is a promising strategy to enhance antitumor immunity.Data are available on reasonable request. Not applicable.