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Clin Cancer Res. 2019 Jun 18. pii: clincanres.0596.2019. doi: 10.1158/1078-0432.CCR-19-0596. [Epub ahead of print]

Rebalancing protein homeostasis enhances tumor antigen presentation.

Author information

1
Koch Institute, Massachusetts Institute of Technology.
2
Biological Engineering, Massachusetts Institute of Technology.
3
Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health.
4
Department of Pathology, Brigham and Women's Hospital.
5
Pathology, Brigham and Women's Hospital, Harvard Medical School.
6
Medical Oncology, Dana-Farber Cancer Institute.
7
Developmental Therapeutics Branch, CCR/NCI, NIH, National Institutes of Health.
8
Department of Biological Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology.
9
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology.
10
Whitehead Institute for Biomedical Research.
11
Department of Molecular Genetics, University of Toronto luke.whitesell@utoronto.ca.

Abstract

PURPOSE:

Despite the accumulation of extensive genomic alterations, many cancers fail to be recognized as "foreign" and escape destruction by the host immune system. Immunotherapies designed to address this problem by directly stimulating immune effector cells have led to some remarkable clinical outcomes, but unfortunately, most cancers fail to respond, prompting the need to identify additional immunomodulatory treatment options.

EXPERIMENTAL DESIGN:

We elucidated the effect of a novel treatment paradigm using sustained, low dose HSP90 inhibition in vitro and in syngeneic mouse models using genetic and pharmacological tools. Profiling of treatment associated tumor cell antigens was performed using immunoprecipitation followed by peptide mass spectrometry.

RESULTS:

We show that sustained, low-level inhibition of HSP90 both amplifies and diversifies the antigenic repertoire presented by tumor cells on MHC-I molecules through an interferon gamma-independent mechanism. In stark contrast, we find that acute, high dose exposure to HSP90 inhibitors, the only approach studied in the clinic to date, is broadly immunosuppressive in cell culture and in cancer patients. In mice, chronic non-heat shock-inducing HSP90 inhibition slowed progression of colon cancer implants, but only in syngeneic animals with intact immune function. Addition of a single dose of non-specific immune adjuvant to the regimen dramatically increased efficacy, curing a subset of mice receiving combination therapy.

CONCLUSIONS:

These highly translatable observations support reconsideration of the most effective strategy for targeting HSP90 to treat cancers and suggest a practical approach to re-purposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy.

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