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- Title
Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1.
- Authors
Park, Jang-June; Thi, Emily P.; Carpio, Victor H.; Bi, Yingzhi; Cole, Andrew G.; Dorsey, Bruce D.; Fan, Kristi; Harasym, Troy; Iott, Christina L.; Kadhim, Salam; Kim, Jin Hyang; Lee, Amy C. H.; Nguyen, Duyan; Paratala, Bhavna S.; Qiu, Ruiqing; White, Andre; Lakshminarasimhan, Damodharan; Leo, Christopher; Suto, Robert K.; Rijnbrand, Rene
- 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. Programmed death-ligand 1 (PD-L1) is involved in the inhibition of antigen specific T cells via ligation of programmed death 1 (PD-1). Here, the authors show checkpoint inhibition by use of small molecule inhibition of PD-L1 which in a humanised mouse model was shown to restore T cell responses and reduced tumour burden.
- Subjects
PROGRAMMED cell death 1 receptors; PROGRAMMED death-ligand 1; ANTIGEN presenting cells; CHRONIC hepatitis B; CANCER treatment; T cells
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-21410-1