Lysosomal degradation of PD-L1 is associated with immune-related adverse events during anti-PD-L1 immunotherapy in NSCLC patients

• DOI: 10.3389/fphar.2024.1384733
• Publication Date: 2024-05-12T21:05:05Z
• Authors: Takeru Kashiwada; Ryotaro Takano; Fumihiko Ando; Shoko Kuroda; Yoshishige Miyabe; Ryuji Owada; Akihiko Miyanaga; Tomoko Asatsuma-O...; Masaaki Hashiguchi; Yoshikazu Kanazawa; Hiroshi Yoshida; Masahiro Seike; Akihiko Gemma; Yoshiko Iwai
• Keywords: Pharmacology; 0301 basic medicine; 03 medical and health sciences; lysosomal degradation; inflammation; immune-related adverse event; macrophage; Therapeutics. Pharmacology; RM1-950; soluble PD-L1

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) non-small cell lung (NSCLC) treated PD-1/PD-L1 blockade their association irAEs. Methods: examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), proinflammatory cytokine levels by plasma samples from 117 GC patients prior surgery 72 NSCLC at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, 24). In mice anti-PD-1/PD-L1 antibodies (Abs), localization of Abs were immunohistochemistry, respectively. Results: was detected higher frequency than patients, whereas similar frequencies patients. correlated IL-1α, IL-1β, TNF-α, IL-6 levels, while MMP13, MMP3, IFN-γ levels. but not anti-PD-1, increased which associated development, clinical outcomes. mice, trafficking anti-PD-L1 lysosomes F4/80 + macrophages resulted production, suppressed lysosomal degradation inhibitor chloroquine macrophage depletion. Conclusion: Anti-PD-L1-mediated induces serve as indicator development during treatment.