Cell Chemical Biology
Volume 28, Issue 2, 18 February 2021, Pages 158-168.e5
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Article
HSP90 Inhibition Enhances Cancer Immunotherapy by Modulating the Surface Expression of Multiple Immune Checkpoint Proteins

https://doi.org/10.1016/j.chembiol.2020.10.005Get rights and content
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Highlights

  • HSP90 inhibition decreases PD-L1 and PD-L2 expression at the protein and mRNA level

  • HSP90 inhibition leads to loss of PD-L1/PD-L2 transcription factors

  • Ganetespib decreases PD-L1 expression in vivo in a syngeneic mouse tumor model

  • PD-L1/PD-L2 expression was decreased in cancer cells and primary human macrophages

Summary

Cancer immunotherapies, including immune checkpoint blockade, have the potential to significantly impact treatments for diverse tumor types. At present, response failures and immune-related adverse events remain significant issues, which could be addressed using optimized combination therapies. Through a cell-based chemical screen of ∼200,000 compounds, we identified that HSP90 inhibitors robustly decrease PD-L1 surface expression, through a mechanism that appears to involve the regulation of master transcriptional regulators (i.e., STAT-3 and c-Myc). Interestingly, HSP90 inhibitors were found to also modulate the surface expression of additional checkpoint proteins (i.e., PD-L2). In the MC-38 syngeneic mouse tumor model, HSP90 inhibition was found to dramatically reduce PD-L1 surface expression on isolated live tumor cells and, consistent with recent findings, was found to increase the number of activated CD8+ T cells within the tumor microenvironment. These findings provide further rationale to explore HSP90 inhibitors as part of combination immunotherapies for the treatment of cancer.

Keywords

Programmed death-ligand 1
Programmed death-ligand 2
heat shock protein 90
phenotypic screening
immune checkpoint protein
immuno-oncology
drug repurposing
flow cytometry-based screening

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These authors contributed equally

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