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

• Published in: Cell chemical biology Vol. 28; no. 2; pp. 158 - 168.e5
• Main Authors: Zavareh, Reza Beheshti, Spangenberg, Stephan H., Woods, Ashley, Martínez-Peña, Francisco, Lairson, Luke L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 18.02.2021
• Subjects: drug repurposing; flow cytometry-based screening; heat shock protein 90; immune checkpoint protein; immuno-oncology; phenotypic screening; Programmed death-ligand 1; Programmed death-ligand 2; drug repurposing; Programmed death-ligand 1; immune checkpoint protein; phenotypic screening; immuno-oncology; Programmed death-ligand 2; flow cytometry-based screening; heat shock protein 90
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2020.10.005

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. [Display omitted] •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 HSP90 inhibitors are found to decrease the expression of immune checkpoint proteins, including PD-L1 and PD-L2, at sub-cytotoxic and clinically relevant concentrations, in cellula in tumor cells and primary human macrophages, as well as in vivo. This suggests that non-toxic doses of an HSP90 inhibitor could enhance cancer immunotherapy.