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

Park, Thi, Carpio, Bi, Cole, Dorsey, Fan, Harasym, Iott, Kadhim, Kim, Lee, Nguyen, Paratala, Qiu, White, Lakshminarasimhan, Leo, Suto, Rijnbrand, Tang, Sofia, Moore (2021) Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1 Nat Commun (IF: 14.7) 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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