Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1

Jang-June Park, Emily Thi, Victor Carpio, Yingzhi Bi, Andrew Cole, Bruce Dorsey, Kristi Fan, Troy Harasym, Christina Iott, Salam Kadhim, Jin Kim, Amy Lee, Duyan Nguyen, Bhavna Paratala, Ruiqing Qiu, Andre White, Damodharan Lakshminarasimhan, Christopher Leo, Robert Suto, Rene Rijnbrand, Sunny Tang, Michael Sofia, Chris Moore (2021) Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1 Nat Commun (IF: 15.7) 12(1) 1222

Abstract

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900207
http://www.ncbi.nlm.nih.gov/pubmed/33619272
http://dx.doi.org/10.1038/s41467-021-21410-1

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