FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells

Nature. 2018 Dec;564(7734):130-135. doi: 10.1038/s41586-018-0756-0. Epub 2018 Nov 28.

Abstract

Dysfunctional T cells in the tumour microenvironment have abnormally high expression of PD-1 and antibody inhibitors against PD-1 or its ligand (PD-L1) have become commonly used drugs to treat various types of cancer1-4. The clinical success of these inhibitors highlights the need to study the mechanisms by which PD-1 is regulated. Here we report a mechanism of PD-1 degradation and the importance of this mechanism in anti-tumour immunity in preclinical models. We show that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells. FBXO38 is an E3 ligase of PD-1 that mediates Lys48-linked poly-ubiquitination and subsequent proteasome degradation. Conditional knockout of Fbxo38 in T cells did not affect T cell receptor and CD28 signalling, but led to faster tumour progression in mice owing to higher levels of PD-1 in tumour-infiltrating T cells. Anti-PD-1 therapy normalized the effect of FBXO38 deficiency on tumour growth in mice, which suggests that PD-1 is the primary target of FBXO38 in T cells. In human tumour tissues and a mouse cancer model, transcriptional levels of FBXO38 and Fbxo38, respectively, were downregulated in tumour-infiltrating T cells. However, IL-2 therapy rescued Fbxo38 transcription and therefore downregulated PD-1 levels in PD-1+ T cells in mice. These data indicate that FBXO38 regulates PD-1 expression and highlight an alternative method to block the PD-1 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • F-Box Proteins / genetics*
  • F-Box Proteins / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Interleukin-2 / immunology
  • Lysine / metabolism
  • Male
  • Melanoma, Experimental / immunology
  • Mice
  • Neoplasms / immunology*
  • Programmed Cell Death 1 Receptor / chemistry
  • Programmed Cell Death 1 Receptor / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment
  • Ubiquitination*

Substances

  • F-Box Proteins
  • FBXO38 protein, human
  • Fbxo38 protein, mouse
  • Interleukin-2
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Proteasome Endopeptidase Complex
  • Lysine