title: Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1.
abstract: T cells play a critical role in tumor immunosurveillance by eliminating newly transformed somatic cells. However, tumor cell variants can escape from immunological control after immunoediting, leading to tumor progression. Whether and how T cells respond to tumor growth remain unclear. Here, we found that tumor-infiltrating T cells exhibited persistently up-regulated expression of the activator protein 1 (AP-1) subunit c-Fos during tumor progression. The ectopic expression of c-Fos in T cells exacerbated tumor growth, whereas the T-cell-specific deletion of c-Fos reduced tumor malignancy. This unexpected immunosuppressive effect of c-Fos was mediated through the induced expression of immune inhibitory receptor programmed death 1 (PD-1) via the direct binding of c-Fos to the AP-1-binding site in the Pdcd1 (gene encoding PD-1) promoter. A knock-in mutation of this binding site abrogated PD-1 induction, augmented antitumor T-cell function and repressed tumor growth. Taken together, these findings indicate that T-cell c-Fos subsequently induces PD-1 expression in response to tumor progression and that disrupting such induction is essential for repression of tumor growth.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xiao
authors.forename: Anqi
authors.initials: A
authors.lastname: Deng
authors.forename: Haifeng
authors.initials: H
authors.lastname: Liu
authors.forename: Gaoxiang
authors.initials: G
authors.lastname: Ge
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D001665:Binding Sites; D018450:Disease Progression; D005434:Flow Cytometry; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation
chemical_list: C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1