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

Chia-Yi Lin1,2, Kuo-Yen Huang3, Shih-Han Kao4

  • 1Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

Science Advances
|April 7, 2023
PubMed

Insights

Researchers discovered PIK-93, a small molecule that enhances PD-L1 immunotherapy for non-small cell lung cancer (NSCLC). This drug modulates the tumor microenvironment (TME) to improve treatment efficacy and immune response against cancer.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Immune checkpoint inhibitors (ICIs) targeting PD-L1 are key treatments for advanced non-small cell lung cancer (NSCLC).
  • Treatment resistance in NSCLC is often linked to an unfavorable tumor microenvironment (TME) and limited antibody penetration.
  • There is a need for strategies to enhance ICI efficacy by modulating the TME.

Purpose of the Study:

  • To identify small-molecule drugs capable of modulating the TME to improve ICI treatment outcomes in NSCLC.
  • To investigate the mechanism by which PIK-93 affects PD-L1 expression and macrophage function.
  • To evaluate the combined efficacy of PIK-93 and anti-PD-L1 antibodies in preclinical NSCLC models.

Main Methods:

  • Utilized a cell-based global protein stability (GPS) screening system to identify PD-L1 modulating small molecules.
  • Investigated PIK-93's mechanism of action, including its effect on PD-L1 ubiquitination and interaction with Cullin-4A.
  • Assessed the impact of PIK-93 on M1 macrophage function and antitumor cytotoxicity in vitro.
  • Evaluated the combined therapeutic effect of PIK-93 and anti-PD-L1 antibodies in syngeneic and xenograft mouse models of NSCLC.

Main Results:

  • Identified PIK-93 as a novel small molecule that reduces PD-L1 levels on M1 macrophages by enhancing PD-L1 ubiquitination.
  • PIK-93 treatment increased M1 macrophage antitumor cytotoxicity.
  • Combination therapy with PIK-93 and anti-PD-L1 antibodies enhanced T cell activation and tumor-infiltrating lymphocyte (TIL) recruitment.
  • Combined treatment significantly inhibited tumor growth in preclinical NSCLC models.

Conclusions:

  • PIK-93 effectively modulates PD-L1 levels and enhances the anti-tumor activity of M1 macrophages.
  • Combining PIK-93 with anti-PD-L1 antibodies creates a more favorable TME, overcoming resistance to ICI therapy.
  • This combination strategy shows significant promise for improving PD-1/PD-L1 blockade immunotherapy in NSCLC.

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