KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression

Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28239-28250. doi: 10.1073/pnas.2004570117. Epub 2020 Oct 27.

Abstract

Aberrant programmed cell death protein 1 (PD-1) expression on the surface of T cells is known to inhibit T cell effector activity and to play a pivotal role in tumor immune escape; thus, maintaining an appropriate level of PD-1 expression is of great significance. We identified KLHL22, an adaptor of the Cul3-based E3 ligase, as a major PD-1-associated protein that mediates the degradation of PD-1 before its transport to the cell surface. KLHL22 deficiency leads to overaccumulation of PD-1, which represses the antitumor response of T cells and promotes tumor progression. Importantly, KLHL22 was markedly decreased in tumor-infiltrating T cells from colorectal cancer patients. Meanwhile, treatment with 5-fluorouracil (5-FU) could increase PD-1 expression by inhibiting the transcription of KLHL22. These findings reveal that KLHL22 plays a crucial role in preventing excessive T cell suppression by maintaining PD-1 expression homeostasis and suggest the therapeutic potential of 5-FU in combination with anti-PD-1 in colorectal cancer patients.

Keywords: 5-FU; PD-1; immune checkpoint block therapy; protein degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / drug effects
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • Fluorouracil
  • HEK293 Cells
  • Homeostasis*
  • Humans
  • Immune Checkpoint Proteins
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Programmed Cell Death 1 Receptor / metabolism*
  • Proteolysis
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • Transcriptome
  • Tumor Microenvironment / immunology
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Immune Checkpoint Proteins
  • KLHL22 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Ubiquitin-Protein Ligases
  • Fluorouracil