Hsp90 inhibition leads to an increase in surface expression of multiple immunological receptors in cancer cells

Abstract

Heat shock protein 90 (Hsp90) is a molecular chaperone important for maintaining protein homeostasis (proteostasis) in the cell. Hsp90 inhibitors are being explored as cancer therapeutics because of their ability to disrupt proteostasis. Inhibiting Hsp90 increases surface density of the immunological receptor Major Histocompatibility Complex 1 (MHC1). Here we show that this increase occurs across multiple cancer cell lines and with both cytosol-specific and pan-Hsp90 inhibitors. We demonstrate that Hsp90 inhibition also alters surface expression of both IFNGR and PD-L1, two additional immunological receptors that play a significant role in anti-tumour or anti-immune activity in the tumour microenvironment. Hsp90 also negatively regulates IFN-γ activity in cancer cells, suggesting it has a unique role in mediating the immune system’s response to cancer. Our data suggests a strong link between Hsp90 activity and the pathways that govern anti-tumour immunity. This highlights the potential for the use of an Hsp90 inhibitor in combination with another currently available cancer treatment, immune checkpoint blockade therapy, which works to prevent immune evasion of cancer cells. Combination checkpoint inhibitor therapy and the use of an Hsp90 inhibitor may potentiate the therapeutic benefits of both treatments and improve prognosis for cancer patients.

Enhancing Magnetic Hyperthermia Efficacy through Targeted Heat Shock Protein 90 Inhibition: Unveiling Immune-Mediated Therapeutic Synergy in Glioma Treatment

“…The secretion of HSPs from the cytoplasm of dead cells during lysis to the extracellular milieu via the bloodstream, , as observed by confocal micrographs in the study, has been reported to facilitate the cross-presentation of antigenic HSP-peptides via MHC class I molecules in dendritic cells (DCs), with subsequent induction of a CD8+ T-cell-mediated adaptive immune response . These activated DCs further induce the release of TNF-α and interferon (IFN), mediated by the NF-κB signaling pathway, which in turn recruits effector CD4+ T-cells and CD8+ T-cells as well as the natural killer (NK) cells.…”