Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity

Bingjie Hao; Shumeng Lin; Haipeng Liu; Junfang Xu; Li Chen; Tiansheng Zheng; Wen Zhang; Yifang Dang; Russel J Reiter; Chaoqun Li; Hong Zhai; Qing Xia; Lihong Fan

doi:10.1080/15548627.2024.2439657

Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity

Autophagy. 2024 Dec 22:1-17. doi: 10.1080/15548627.2024.2439657. Online ahead of print.

Authors

Bingjie Hao^{1

2}, Shumeng Lin^{1

2}, Haipeng Liu³, Junfang Xu³, Li Chen³, Tiansheng Zheng², Wen Zhang², Yifang Dang⁴, Russel J Reiter⁵, Chaoqun Li¹, Hong Zhai², Qing Xia¹, Lihong Fan^{1

2

6}

Affiliations

¹ Institute of Energy Metabolism and Health, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
² Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
³ Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁴ Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁵ Department of Cell Systems and Anatomy, University of Texas Health San Antonio, San Antonio, TX, USA.
⁶ Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.

PMID: 39710370
DOI: 10.1080/15548627.2024.2439657

Abstract

Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable. Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation. Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274. Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity. Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular "glue" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.Abbreviations: ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A₁; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.

Keywords: Antitumor immunity; CD274; MAP1LC3B; autophagy; baicalein; protein degradation.