The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment

Abstract Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. Here, we show that the number of Treg cells are selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3high effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8+ T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL-2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the TME by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell–targeted cancer immunotherapy.