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HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes

Author

Listed:
  • Rina M. Mbofung

    (The University of Texas MD Anderson Cancer Center)

  • Jodi A. McKenzie

    (The University of Texas MD Anderson Cancer Center)

  • Shruti Malu

    (The University of Texas MD Anderson Cancer Center)

  • Min Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Weiyi Peng

    (The University of Texas MD Anderson Cancer Center)

  • Chengwen Liu

    (The University of Texas MD Anderson Cancer Center)

  • Isere Kuiatse

    (The University of Texas MD Anderson Cancer Center)

  • Trang Tieu

    (The University of Texas MD Anderson Cancer Center)

  • Leila Williams

    (The University of Texas MD Anderson Cancer Center)

  • Seram Devi

    (The University of Texas MD Anderson Cancer Center)

  • Emily Ashkin

    (The University of Texas MD Anderson Cancer Center)

  • Chunyu Xu

    (The University of Texas MD Anderson Cancer Center)

  • Lu Huang

    (The University of Texas MD Anderson Cancer Center)

  • Minying Zhang

    (The University of Texas MD Anderson Cancer Center)

  • Amjad H. Talukder

    (The University of Texas MD Anderson Cancer Center)

  • Satyendra C. Tripathi

    (The University of Texas MD Anderson Cancer Center)

  • Hiep Khong

    (The University of Texas MD Anderson Cancer Center)

  • Nikunj Satani

    (The University of Texas MD Anderson Cancer Center)

  • Florian L. Muller

    (The University of Texas MD Anderson Cancer Center)

  • Jason Roszik

    (The University of Texas MD Anderson Cancer Center)

  • Timothy Heffernan

    (The University of Texas MD Anderson Cancer Center)

  • James P. Allison

    (The University of Texas MD Anderson Cancer Center)

  • Gregory Lizee

    (The University of Texas MD Anderson Cancer Center)

  • Sam M. Hanash

    (The University of Texas MD Anderson Cancer Center)

  • David Proia

    (Synta Pharmaceuticals Inc.)

  • Rodabe Amaria

    (The University of Texas MD Anderson Cancer Center)

  • R. Eric Davis

    (The University of Texas MD Anderson Cancer Center)

  • Patrick Hwu

    (The University of Texas MD Anderson Cancer Center)

Abstract

T-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.

Suggested Citation

  • 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 Zhan, 2017. "HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes," Nature Communications, Nature, vol. 8(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00449-z
    DOI: 10.1038/s41467-017-00449-z
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