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Review
. 2020 Aug 15;17(3):583-598.
doi: 10.20892/j.issn.2095-3941.2020.0066.

Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

Affiliations
Review

Proteasomal and lysosomal degradation for specific and durable suppression of immunotherapeutic targets

Yungang Wang et al. Cancer Biol Med. .

Abstract

Cancer immunotherapy harness the body's immune system to eliminate cancer, by using a broad panel of soluble and membrane proteins as therapeutic targets. Immunosuppression signaling mediated by ligand-receptor interaction may be blocked by monoclonal antibodies, but because of repopulation of the membrane via intracellular organelles, targets must be eliminated in whole cells. Targeted protein degradation, as exemplified in proteolysis targeting chimera (PROTAC) studies, is a promising strategy for selective inhibition of target proteins. The recently reported use of lysosomal targeting molecules to eliminate immune checkpoint proteins has paved the way for targeted degradation of membrane proteins as crucial anti-cancer targets. Further studies on these molecules' modes of action, target-binding "warheads", lysosomal sorting signals, and linker design should facilitate their rational design. Modifications and derivatives may improve their cell-penetrating ability and the in vivo stability of these pro-drugs. These studies suggest the promise of alternative strategies for cancer immunotherapy, with the aim of achieving more potent and durable suppression of tumor growth. Here, the successes and limitations of antibody inhibitors in cancer immunotherapy, as well as research progress on PROTAC- and lysosomal-dependent degradation of target proteins, are reviewed.

Keywords: Cancer immunotherapy; PROTAC; membrane protein; targeted degradation.

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Figures

Figure 1
Figure 1
Subcellular transportation of PD-L1 and actions of anti-PD-L1 antibody. The antibody drug binds PD-L1 expressed on the tumor cell surface, thereby blocking its interaction with PD-1. PD-L1 is degraded in the lysosome, in a process relying on several subcellular transport steps from the cell membrane to the endosome, and finally to the lysosome. PD-L1 can also be transported to recycling endosomes, thus decreasing the distribution to late endosomes and lysosomes. PD-L1 is delivered to late endosomes and then sorted to lysosomes via multivesicular bodies (MVBs) for degradation.
Figure 2
Figure 2
The modes of action of PROTACs and lysosomal targeting molecules. (A) PROTACs can bind target proteins and E3 ligase, thus forming a target protein-PROTAC-E3 ligase ternary complex, which places the target protein and E3 ligase in proximity. Ubiquitin is then transferred from E3 ligase to the target protein. Finally, the target protein is completely degraded through the action of protease. (B) The lysosomal targeting construct contains 2 functional regions: one binds with the target protein, and the other anchors to ALIX and ESCRT for delivery to multivesicular bodies (MVB) and lysosomes.

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References

    1. Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science. 2020:367. Doi: 10.1126/science.aax0182. In press. - PMC - PubMed
    1. Heyman B, Yang YP. New developments in immunotherapy for lymphoma. Cancer Biol Med. 2018;15:189–209. - PMC - PubMed
    1. Muir C, Menzies AM, Clifton-Bligh RJ, Tsang VHM. Thyroid toxicity following immune checkpoint inhibitor treatment in advanced cancer. Thyroid. 2020 Doi: 10.1089/thy.2020.0032. In press. - PubMed
    1. Park JG, Lee CR, Kim MG, Kim G, Shin HM, Jeon YH, et al. Kidney residency of VISTA-positive macrophages accelerates repair from ischemic injury. Kidney Int. 2019;97:980–94. - PubMed
    1. Okoye IS, Xu L, Walker J, Elahi S. The glucocorticoids prednisone and dexamethasone differentially modulate T cell function in response to anti-PD-1 and anti-CTLA-4 immune checkpoint blockade. Cancer Immunol Immunother. 2020 Doi: 10.1007/s00262-020-02555-2. In press. - PMC - PubMed

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