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

作者：Jang‐June Park, Emily P. Thi, Victor H. Carpio, Yingzhi Bi, Andrew G. Cole, Bruce D. Dorsey, Kristi Fan, Troy O. Harasym, Christina L. Iott, Salam Kadhim, Jin Hyang Kim, Amy C. H. Lee, Duyan Nguyen, Bhavna Paratala, Ruiqing Qiu, André White, L. Damodharan, Christopher Leo, R.K. Suto, René Rijnbrand, Sunny X. Tang, Michael J. Sofia, Chris B. Moore · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-21410-1 · 被引用次数：137 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Immune Cell Function and Interaction

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.