Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation.

TitleRebalancing Protein Homeostasis Enhances Tumor Antigen Presentation.
Publication TypeJournal Article
Year of Publication2019
AuthorsJaeger AM, Stopfer L, Lee S, Gaglia G, Sandel D, Santagata S, Lin NU, Trepel JB, White F, Jacks T, Lindquist S, Whitesell L
JournalClin Cancer Res
Volume25
Issue21
Pagination6392-6405
Date Published2019 Nov 01
ISSN1078-0432
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. We elucidated the effect of a novel treatment paradigm using sustained, low-dose HSP90 inhibition and in syngeneic mouse models using genetic and pharmacologic 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 IFN╬│-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 patients with cancer. 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 nonspecific 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 repurposing current orally bioavailable HSP90 inhibitors as a new immunotherapeutic strategy..

DOI10.1158/1078-0432.CCR-19-0596
Alternate JournalClin. Cancer Res.
PubMed ID31213460
PubMed Central IDPMC6825536
Grant ListP30 CA014051 / CA / NCI NIH HHS / United States
R01 CA194005 / CA / NCI NIH HHS / United States