Targeting Heat-Shock Protein 90 (HSP90) As a Complementary Strategy to Immune Checkpoint Blockade for Cancer Therapy

The demonstration that immune checkpoint blockade can meaningfully improve outcomes for cancer patients has revolutionized the field of immuno-oncology. New biologic agents targeting specific checkpoints have shown remarkable durability in terms of patient response and, importantly, exhibit clinical activity across a range of human malignancies, including many that have traditionally proven refractory to other immunotherapies. In this rapidly evolving area, a key consideration relates to the identification of novel combinatorial strategies that exploit existing or investigational cancer therapies in order to optimize patient outcomes and the proportion of individuals able to derive benefit from this approach. In this regard, heat-shock protein 90 (HSP90) represents an important emerging target for cancer therapy because its inactivation results in the simultaneous blockade of multiple signaling pathways and can sensitize tumor cells to other anticancer agents. Within the context of immunology, HSP90 plays a dual regulatory role, with its functional inhibition resulting in both immunosuppressive and immunostimulatory effects. In this Cancer Immunology at the Crossroads overview, the anticancer activity profile of targeted HSP90 inhibitors is discussed along with their paradoxical roles in immunology. Overall, we explore the rationale for combining the modalities of HSP90 inhibition and immune checkpoint blockade in order to augment the antitumor immune response in cancer.