@article {Liue005116, author = {Jiaxin Liu and Lingyun Wei and Nan Hu and Dong Wang and Juan Ni and Sha Zhang and Hongbing Liu and Tangfeng Lv and Jie Yin and Mingxiang Ye and Yong Song}, title = {FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer}, volume = {10}, number = {9}, elocation-id = {e005116}, year = {2022}, doi = {10.1136/jitc-2022-005116}, publisher = {BMJ Specialist Journals}, abstract = {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 {\textquoteleft}hot{\textquoteright} 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.}, URL = {https://jitc.bmj.com/content/10/9/e005116}, eprint = {https://jitc.bmj.com/content/10/9/e005116.full.pdf}, journal = {Journal for ImmunoTherapy of Cancer} }