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

Proceedings of the National Academy of Sciences of the United States of America 2020 Nov 10

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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.

Citation

Xiao Albert Zhou, Jiadong Zhou, Long Zhao, Guihui Yu, Jun Zhan, Chanyi Shi, Ruoshi Yuan, Yan Wang, Changfeng Chen, Wenjia Zhang, Donghao Xu, Yingjiang Ye, Weibin Wang, Zhanlong Shen, Wei Wang, Jiadong Wang. KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression. Proceedings of the National Academy of Sciences of the United States of America. 2020 Nov 10;117(45):28239-28250