Published on Fri Sep 17 2021

Therapeutic anti-PD-L1 antibody affects ESCRT-mediated functions in cells expressing oncogenic EGFR.

Letian, A., Yemanaberhan, E., Cavaliere, P., Dephoure, N., Altorki, N. K., McGraw, T. E.

Anti-PD-L1 antibody is an effective therapy for a variety of solid tumors. For unknown reasons, EGFR-mutant tumors respond poorly to checkpoint blockade. Study reveals new cell-intrinsic roles for PD-L 1 in EGFR mutant cells.

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Abstract

PD-L1 is a ligand for immune checkpoint receptor PD1. Anti-PD-L1 antibody is an effective therapy for a variety of solid tumors, although a durable response is only achieved in a subset of patients. For unknown reasons, EGFR-mutant tumors respond poorly to checkpoint blockade. Applying quantitative cell biological methods to study PD-L1 biology in lung cancer cells, we establish that growth factors acutely regulate PD-L1 trafficking between the plasma membrane and the interior of cells. Changes in plasma membrane PD-L1 levels will impact PD1 engagement on T cells, thereby influencing PD-L1's immune suppressive activity. To discover potential cell-intrinsic functions of PD-L1, we used APEX2 biotinylation to generate a high-resolution map of the PD-L1 proximal proteome. ESCRT pathway proteins were enriched in PD-L1's proximal proteome, and two ESCRT-dependent functions, turnover of mutant EGFR and biogenesis of extracellular vesicles, were affected by anti-PD-L1 treatment, suggesting a link between PD-L1 and ESCRT function. Proteins that control cytoskeletal dynamics were also enriched in the PD-L1 proteome, and anti-PD-L1 treatment reduced cell migration, identifying migration as a PD-L1 associated function. PD-L1 knockout mimics the effects of the antibody treatment, suggesting anti-PD-L1 antibody effects are loss of function(s). The effects of anti-PD-L1 on the ESCRT-dependent functions and cell migration were restricted to cells harboring oncogenic EGFR mutations. Wildtype and KRAS mutant cells lines were unaffected. Our study reveals new cell-intrinsic roles for PD-L1 in EGFR mutant cells, activities that might contribute to the resistance of EGFR mutant tumors to PD-L1 checkpoint blockade.