Dr. Yang, Pan-Chyr 's publons link picture

Dr. Yang, Pan-Chyr

Joint Appointment Research Fellow
Academician, Academia Sinica
  • 02-27899149 (Lab) (Room No: 511)
  • 02-27858594 (Fax)

Specialty:
  • Cell and Molecular Biology
  • Cancer genomics

Education and Positions:
  • M.D., Ph.D. National Taiwan University


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

Dr. Yang, Pan-Chyr
Science Advances, Apr 07, 2023

 

 

 

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.