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

Significance Aberrant PD-1 expression is known to inhibit T cell effector activity and plays a pivotal role in tumor immune escape. Since maintaining an appropriate level of PD-1 expression is of great significance, it should be highly regulated at multiple levels. Despite extensive studies to date on this topic, it remains unclear how PD-1 expression is precisely regulated at the posttranslation level both during T cell activation and among the tumor microenvironment. Here, we show that KLHL22 maintains PD-1 protein homeostasis by degrading incompletely glycosylated PD-1, thereby preventing excessive T cell suppression. KLHL22-mediated degradation of PD-1 protein will be ineffective in response to either the tumor microenvironment or treatment with 5-FU, resulting in excessive PD-1 accumulation and reduced T cell activity. 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.