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Updated: Sep 25, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Targeting HSP90 sensitizes pancreas carcinoma to PD-1 blockade
Jiao Liu1, Rui Kang2, Guido Kroemer3,4,5
1DAMP Laboratory, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong China.
Abstract:
Interferon gamma (IFNG/IFNγ)-induced adaptive immune resistance remains a challenge for tumor therapy. We observed that the chaperone heat shock protein 90 (HSP90) stabilizes the transcription factor signal transducer and activator of transcription 1 (STAT1), resulting in IFNγ-induced expression of immunosuppressive indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1/CD274). Pharmacological inhibition of HSP90 enhances the efficacy of programmed cell death 1 (PDCD1/PD-1) targeting immunotherapy in suitable mouse models without any toxicity.
Insights
Heat shock protein 90 (HSP90) inhibition overcomes tumor immune resistance by blocking interferon gamma (IFNγ)-induced immunosuppression. This approach enhances anti-PD-1 immunotherapy efficacy in mouse models without toxicity.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Interferon gamma (IFNγ)-induced adaptive immune resistance is a significant hurdle in effective tumor therapy.
- Heat shock protein 90 (HSP90) plays a crucial role in stabilizing key transcription factors involved in immune regulation.
Purpose of the Study:
- To investigate the role of HSP90 in IFNγ-induced immunosuppression in the tumor microenvironment.
- To evaluate the therapeutic potential of HSP90 inhibition in combination with immunotherapy.
Main Methods:
- Analysis of HSP90's interaction with signal transducer and activator of transcription 1 (STAT1) in response to IFNγ.
- Assessment of IFNγ-induced immunosuppressive molecules, indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1/CD274) expression.
- Pharmacological inhibition of HSP90 and evaluation of its impact on anti-programmed cell death 1 (PD-1) immunotherapy efficacy in mouse tumor models.
Main Results:
- HSP90 was found to stabilize STAT1, leading to increased expression of immunosuppressive IDO1 and PD-L1 upon IFNγ stimulation.
- Pharmacological inhibition of HSP90 effectively reduced IFNγ-induced immunosuppressive markers.
- HSP90 inhibition significantly enhanced the efficacy of PD-1 targeting immunotherapy in preclinical mouse models.
Conclusions:
- Targeting HSP90 represents a viable strategy to overcome adaptive immune resistance in cancer therapy.
- Combined inhibition of HSP90 and PD-1 immunotherapy offers a promising, non-toxic approach to improve tumor treatment outcomes.
