HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes

• DOI: 10.1038/s41467-017-00449-z
• Publication Date: 2017-08-31T10:17:24Z
• Authors: Rina M. Mbofung; Jodi A. McKenzie; Shruti Malu; Min Zhang; Weiyi Peng; Chengwen Liu; Isere Kuiatse; Trang Tieu; Leila Williams; Seram Devi; Emily Ashkin; Chunyu Xu; Lu Huang; Minying Zhang; Amjad H. Talukder; Satyendra C. Trip...; Hiep Khong; Nikunj Satani; Florian L. Muller; Jason Roszik; Timothy Heffernan; James P. Allison; Gregory Lizee; Sam M. Hanash; David Proia; Rodabe Amaria; R. Eric Davis; Patrick Hwu
• Keywords: 0301 basic medicine; Science; Gene Expression Profiling; T-Lymphocytes; Q; Kaplan-Meier Estimate; Triazoles; Ipilimumab; Xenograft Model Antitumor Assays; Article; Tumor Burden; Up-Regulation; 3. Good health; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Female; HSP90 Heat-Shock Proteins; Immunotherapy; Interferons; Melanoma

AbstractT-cell-based immunotherapies are promising treatments for cancer patients. Although durable responses can be achieved in some patients, many patients fail to respond to these therapies, underscoring the need for improvement with combination therapies. From a screen of 850 bioactive compounds, we identify HSP90 inhibitors as candidates for combination with immunotherapy. We show that inhibition of HSP90 with ganetespib enhances T-cell-mediated killing of patient-derived human melanoma cells by their autologous T cells in vitro and potentiates responses to anti-CTLA4 and anti-PD1 therapy in vivo. Mechanistic studies reveal that HSP90 inhibition results in upregulation of interferon response genes, which are essential for the enhanced killing of ganetespib treated melanoma cells by T cells. Taken together, these findings provide evidence that HSP90 inhibition can potentiate T-cell-mediated anti-tumor immune responses, and rationale to explore the combination of immunotherapy and HSP90 inhibitors.