The role of the HSP90 chaperone in immune checkpoint expression and resistance to immunotherapy

In the past decade immune checkpoint blockade (ICB) immunotherapy has represented a successful strategy for anti-cancer treatment, as it re-activates the immune responses against neoplastic cells. However, different forms of resistance to ICB have been described. The underlying molecular mechanisms are still unclear and their comprehension is of primary importance in uncovering new strategies to overcome resistance. In that context, the heat shock protein 90 (HSP90) has aroused great interest. It mediates the transcriptional upregulation of diverse immune checkpoint proteins, thus promoting their membrane exposition. By inhibiting HSP90, even if immune checkpoint proteins are less expressed, an increased cytotoxic T lymphocyte activity against neoplastic cells has been reported, ameliorating ICB outcomes. Moreover, HSP90 mediates resistance to ICB treatment, by activating survival signaling pathways in cancer cells and promoting the secretion of immunosuppressive metabolites. These data collectively demonstrate that the combinatorial administration of HSP90 inhibitors with ICB immunotherapy could represent a promising field of investigation in trying to overcome resistance.