Editors' ChoiceImmunology

Targeting PD-1

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Science Signaling  11 Dec 2018:
Vol. 11, Issue 560, eaaw3120
DOI: 10.1126/scisignal.aaw3120

Loss of an E3 ubiquitin ligase that targets PD-1 for degradation leads to inefficient antitumor responses by T cells.

The abundance of the inhibitory receptor programmed cell death 1 (PD-1) on T cells is increased by chronic exposure to antigens, which leads to T cell exhaustion and dysfunction. Antibodies that block PD-1 or its ligand PD-L1 have proven successful as therapies to enhance the antitumor activity of T cells in some patients. Meng et al. found that the activation of human and mouse T cells transiently increased the cell surface abundance of PD-1; however, there was little change in mRNA abundance. Instead, T cell activation stimulated PD-1 internalization, ubiquitylation, and degradation in a proteasome-dependent manner. Coimmunoprecipitation experiments showed that the E3 ubiquitin ligase FBXO38 physically interacted with PD-1 and mediated its Lys48-linked polyubiquitylation and degradation. Conditional knockout of Fbxo38 in mouse T cells (Fbxo38CKO mice) did not affect T cell activation through the T cell receptor (TCR) but did enhance the cell surface abundance of PD-1 after TCR stimulation. In two different cancer models, tumors grew faster in Fbxo38CKO mice than in wild-type mice, and tumor-infiltrating CD8+ T cells in the Fbxo38CKO mice had increased PD-1 abundance. These results were recapitulated in adoptive transfer experiments with T cells in which Fbxo38 was knocked down (Fbxo38KD cells). The defective antitumor activity of the Fbxo38KD cells was rescued with a PD-1 inhibitory antibody. In human cancer samples, the expression of FBXO38 was reduced in tumor-infiltrating CD8+ T cells compared with that in CD8+ T cells in peripheral blood. In mouse and human T cells, the cytokine interleukin-2 (IL-2) dose-dependently increased the expression of Fbxo38 and FBXO38, respectively. Treating mice with IL-2 increased the expression of Fbxo38 in tumor-infiltrating CD8+ T cells, reduced their cell surface abundance of PD-1, and enhanced their antitumor activity. Together, these data suggest that the E3 ligase FBXO38 specifically targets PD-1 for degradation in activated T cells; thus, targeting this pathway may modulate antitumor immunity.

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