Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1

Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15419-24. doi: 10.1073/pnas.1206370109. Epub 2012 Sep 4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Disease Progression
  • Flow Cytometry
  • Gene Deletion
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neoplasm Transplantation
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Programmed Cell Death 1 Receptor / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-fos / metabolism
  • T-Lymphocytes / cytology*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / physiology*
  • Transcriptional Activation

Substances

  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-fos
  • Transcription Factor AP-1