Fig. HIP1R and a rationally designed PD-LYSO peptide targets PD-L1 to lysosomal degradation

Jie Xu, a researcher from Shanghai Jiaotong University, supported by the National Natural Science Foundation of China (Grant No. 81572326, 81322036, 81320108024), has made important progress in the study of PD-L1 lysosomal degradation and its regulation mechanism. The research result was published online in Nature Chemical Biology on November 5, 2018, titled ‘ HIP1R targets PD-L1 lysosomal degradation to regulate T cell-mediated cytotoxicity ’( Weblink: https://www.nature.com/articles/s41589-018-0161-x). Jie Xu is the corresponding author of the paper; and Huanbin Wang, a PhD student of Shanghai Jiaotong University, is the first author.

Immune checkpoints are inhibitory signaling regulators of human immune system, which can regulate the intensity and duration of immune response, avoid tissue damage and maintain body self-tolerance. Tumors can utilize the inhibitory effect of immune checkpoint pathway to avoid the recognition of the immune cells, especially to inhibit the T cell–mediated immune surveillance, so as to achieve immune escape. Therefore, suppression of the immune checkpoint molecules can stimulate the original anti-tumor potential of the immune system. At present, inhibitory checkpoint molecules targeted for cancer immunotherapy are mainly focused on CTLA-4, PD1 and PD-L1, and immune checkpoint blockade (ICB) therapies targeting PD-1 and PD-L1 have exhibited significant clinical benefits. However, the relatively low response rate and acquired ICB resistance after long time use still need to be addressed. The expression of PD-L1 on the surface of tumor cells and other cells in tumor microenvironment has an important influence on the efficacy of ICB therapy. Thus, it is essential to understand the molecular regulation of PD-L1 in these cells to enhance the antitumor effect of immunotherapy.

Jie Xu and his research team identified HIP1R as a negative regulator of PD-L1 and showed that HIP1R targeted PD-L1 to lysosomal degradation. They found that HIP1R physically interacted with PD-L1 and delivered PD-L1 to the lysosome through a lysosomal targeting signal. Depletion of HIP1R in tumor cells caused PD-L1 accumulation and suppressed T cell–mediated cytotoxicity. By dissecting the motifs of HIP1R required for regulating PD-L1, the team identified a ‘binding–sorting’ model for the targeted delivery of PD-L1 to the lysosome. This mechanism guided the design of a chimeric peptide (PD-LYSO), which fused the PD-L1-binding sequence of HIP1R to a previously reported lysosome sorting signal sequence, and they verified that the rationally designed PD-LYSO peptide could bind to PD-L1 and mediate PD-L1 to lysosome for degradation in cancer cells.

Xu’s research team has obtained patent for the PD-LYSO polypeptide; and pre-clinical study is in progress as well. Different from the current widely used ICB therapy, such as PD-1or PD-L1 antibodies, the rationalized design of chimeric PD-LYSO peptide for targeted degradation of PD-L1 exemplified a strategy for depleting a membrane protein by harnessing the lysosomal proteolytic system. This research indicates a potential new route for regulatory mechanism of PD-L1, and provides a new target and strategy for antitumor immunotherapy.