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HSP90 Inhibition Enhances Cancer Immunotherapy by Modulating the Surface Expression of Multiple Immune Checkpoint

Reza Beheshti Zavareh1, Stephan H Spangenberg2, Ashley Woods3

  • 1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; California Institute for Biomedical Research, 11119 North Torrey Pines Road, La Jolla, CA 92037, USA.

Cell Chemical Biology
|October 28, 2020
PubMed

Insights

Heat shock protein 90 (HSP90) inhibitors reduce PD-L1 expression on cancer cells, enhancing anti-tumor immunity. This suggests HSP90 inhibitors are promising for combination cancer immunotherapy.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Cancer immunotherapies, such as immune checkpoint blockade, show promise but face challenges like treatment failures and adverse events.
  • Optimized combination therapies are needed to overcome limitations in current cancer treatments.

Purpose of the Study:

  • To identify novel therapeutic strategies for enhancing cancer immunotherapy.
  • To investigate the effect of HSP90 inhibitors on immune checkpoint protein expression and anti-tumor immune responses.

Main Methods:

  • Conducted a cell-based chemical screen of approximately 200,000 compounds.
  • Utilized the MC-38 syngeneic mouse tumor model.
  • Analyzed surface expression of PD-L1 and PD-L2 on tumor cells and immune cell populations.

Main Results:

  • HSP90 inhibitors significantly decreased surface expression of PD-L1 and PD-L2 on tumor cells.
  • HSP90 inhibition downregulates PD-L1 via regulation of STAT-3 and c-Myc.
  • HSP90 inhibition increased the number of activated CD8+ T cells within the tumor microenvironment in the MC-38 model.

Conclusions:

  • HSP90 inhibitors demonstrate a novel mechanism for reducing PD-L1 expression, a key immune checkpoint.
  • These findings support the exploration of HSP90 inhibitors in combination with other cancer immunotherapies to improve treatment efficacy.
Keywords:
Programmed death-ligand 1Programmed death-ligand 2drug repurposingflow cytometry-based screeningheat shock protein 90immune checkpoint proteinimmuno-oncologyphenotypic screening

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