HIP1R targets PD-L1 for lysosomal degradation, thereby enhancing the antitumor activity of T cells.

  • Major finding: HIP1R targets PD-L1 for lysosomal degradation, thereby enhancing the antitumor activity of T cells.

  • Approach: A peptide with the lysosome-sorting signal and PD-L1 binding sequence of HIP1R targets PD-L1 for degradation.

  • Impact: Chimeric peptides designed to promote PD-L1 degradation may be beneficial to enhance antitumor immunity.

Immune checkpoint blockade therapies targeting PD-1 or PD-L1 have demonstrated clinical success in a variety of tumor types, but the responses are rarely durable and some patients do not respond at all. The available anti–PD-L1 antibodies target tumor cell surface protein, but do not affect intracellular levels. Regulators of PD-L1 expression may serve as potential therapeutic targets. PD-L1 expression has been reported to be regulated by lysosome-dependent degradation, but the mechanism has not been fully elucidated. Wang and colleagues used a combined genomic and proteomic discovery model termed OncoBinder to identify potential regulators of PD-L1. This approach uncovered a gene involved in cellular logistics, huntingtin interacting protein 1-related (HIP1R), as the gene most negatively associated with PD-L1 status, with tumors with PD-L1 copy gain exhibiting an increased propensity toward HIP1R loss. In multiple tumor cell lines, depleting HIP1R resulted in upregulation of PD-L1, indicating that HIP1R is a negative regulator of PD-L1. HIP1R did not affect PD-L1 mRNA expression, but instead promoted lysosomal degradation of PD-L1. HIP1R-dependent degradation of PD-L1 resulted in reduced binding to PD-1 on T cells, thereby enhancing the antitumor activity of T cells. HIP1R bound to the C-terminal tail of PD-L1 through a conserved C-terminal domain, and a C-terminal sorting motif in HIP1R was required to direct lysosomal proteolysis of PD-L1. These findings guided the design of a peptide (PD-LYSO) aimed at triggering PD-L1 degradation. PD-LYSO contained the lysosome-sorting signal and the PD-L1 binding sequencing of HIP1R. As expected, PD-LYSO reduced PD-L1 expression by accelerating its degradation, an effect that could be blocked with a lysosomal inhibitor. In addition to identifying HIP1R as a negative regulator of PD-L1, these findings suggest the potential for the design of anticancer therapies that target PD-L1 for degradation.

Wang H, Yao H, Li C, Shi H, Lan J, Li Z, et al. HIP1R targets PD-L1 to lysosomal degradation to alter T cell-mediated cytotoxicity. Nat Chem Biol 2018;15:42–50.

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