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 cancer1,2,3,4. 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
We thank C. Li for biochemical support; Y. Gao and B. Li for providing FOXP3-expressing Jurkat cells; A. Bietz for proofreading; X. Shi, C. Yan and J. Zhang for discussion; Genome Tagging Project (GTP) Center, Animal facility and Cell Biology facility of SIBCB for technical support. C.X. is funded by NSFC grants (31530022, 31425009, 31621003), CAS grants (Strategic Priority Research Program XDB08020100, XDB29000000; Facility-based Open Research Program; QYZDB-SSW-SMC048), STSMC 16JC1404800 and the Ten Thousand Talent Program ‘National Program for Support of Top-notch Young Professionals’ of China.
Nature thanks R. Deshaies, W. Ouyang, K. Paukan and the other anonymous reviewer(s) for their contribution to the peer review of this work.