2. Academic Validation
  3. Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response

Small-molecule PIK-93 modulates the tumor microenvironment to improve immune checkpoint blockade response

  • Sci Adv. 2023 Apr 7;9(14):eade9944. doi: 10.1126/sciadv.ade9944.
Chia-Yi Lin 1 2,  Kuo-Yen Huang 3,  Shih-Han Kao 4,  Ming-Shiu Lin 1 2,  Chih-Chien Lin 1 2,  Shuenn-Chen Yang 2,  Wei-Chia Chung 1 2,  Ya-Hsuan Chang 5,  Rong-Jie Chein 6,  Pan-Chyr Yang 1 2 7
Affiliations

Affiliations

  • 1 Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
  • 2 Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei 115, Taiwan.
  • 3 Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 4 Resuscitation Science Center of Emphasis, Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 5 Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
  • 6 Institute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan.
  • 7 Genomics Research Center, Academia Sinica, Nankang, Taipei 115, Taiwan.
PMID: 37027467 DOI: 10.1126/sciadv.ade9944
Abstract

Immune checkpoint inhibitors (ICIs) targeting PD-L1 immunotherapy are state-of-the-art treatments for advanced non-small cell lung Cancer (NSCLC). However, the treatment response of certain patients with NSCLC is unsatisfactory because of an unfavorable tumor microenvironment (TME) and poor permeability of antibody-based ICIs. In this study, we aimed to discover small-molecule drugs that can modulate the TME to enhance ICI treatment efficacy in NSCLC in vitro and in vivo. We identified a PD-L1 protein-modulating small molecule, PIK-93, using a cell-based global protein stability (GPS) screening system. PIK-93 mediated PD-L1 ubiquitination by enhancing the PD-L1-Cullin-4A interaction. PIK-93 reduced PD-L1 levels on M1 macrophages and enhanced M1 antitumor cytotoxicity. Combined PIK-93 and anti-PD-L1 antibody treatment enhanced T cell activation, inhibited tumor growth, and increased tumor-infiltrating lymphocyte (TIL) recruitment in syngeneic and human peripheral blood mononuclear cell (PBMC) line-derived xenograft mouse models. PIK-93 facilitates a treatment-favorable TME when combined with anti-PD-L1 Antibodies, thereby enhancing PD-1/PD-L1 blockade Cancer Immunotherapy.

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