The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma.

Autor:	Nieto C; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Miller B; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Alzofon N; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Chimed T; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Himes J; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Joshi M; Department of Pharmacology, UCDSOM, Aurora, CO, USA., Gomez K; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Chowdhury FN; Department of Otolaryngology, UCDSOM, Aurora, CO, USA., Le PN; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Weaver A; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Somerset H; Department of Pathology, UCDSOM, Aurora, CO, USA., Morton JJ; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Wang JH; Department of Immunology and Microbiology, UCDSOM, Aurora, CO, USA.; University of Pittsburgh Medical Center Hillman Cancer Center, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA., Wang XJ; Department of Pathology, UCDSOM, Aurora, CO, USA.; Department of Pathology, University of California Davis, Davis, CA, USA., Gao D; Department of Pediatrics, UCDSOM, Aurora, CO, USA., Hansen K; Department of Biochemistry and Molecular Genetics, UCDSOM, Aurora, CO, USA., Keysar SB; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA., Jimeno A; Division of Medical Oncology, Department of Medicine, University of Colorado Denver, School of Medicine (UCDSOM), Aurora, CO, USA.; Gates Center for Regenerative Medicine, UCDSOM, Aurora, CO, USA.
Jazyk:	angličtina
Zdroj:	Journal of the National Cancer Institute [J Natl Cancer Inst] 2023 Nov 08; Vol. 115 (11), pp. 1392-1403.
DOI:	10.1093/jnci/djad126
Abstrakt:	Background: The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood. Methods: We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1-ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion. To determine how PD-L1 transduces signals intracellularly, we used the BioID2 platform to identify the PD-L1 intracellular interactome. Both human papillomavirus-positive and negative patient-derived xenografts were implanted in NOD-scid-gamma and humanized mouse models to investigate the effects of recombinant PD-1, anti-PD-L1, and anti-signal transducer and activator of transcription 3 (STAT3) in vivo. Results: PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell-intrinsic signaling. PD-L1 binding partners interleukin enhancer binding factors 2 and 3 (ILF2-ILF3) transduced their effect through STAT3. Δ260-290PD-L1 disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T-cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control. Conclusions: Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T-cell function while simultaneously enhancing cancer cell-invasive properties. (© The Author(s) 2023. Published by Oxford University Press.)
Databáze:	MEDLINE
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