HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes

Mbofung, Rina M.; McKenzie, Jodi A.; Malu, Shruti; Zhang, Min; Peng, Weiyi; Liu, Chengwen; Kuiatse, Isere; Tieu, Trang N.; Williams, Leila J.; Devi, Seram; Ashkin, Emily L.; Xu, Chunyu; Huang, Lu; Zhang, Minying; Talukder, Amjad H.; Tripathi, Satyendra Chandra; Khong, Hiep; Satani, Nikunj; Muller, Florian L.; Roszik, Jason; Heffernan, Timothy P.; Allison, James P.; Lizee, Gregory; Hanash, Sam; Proia, David A.; Amaria, Rodabe N.; Davis, R. Eric; Hwu, Patrick

doi:10.1038/s41467-017-00449-z

Cited by 106 publications

(82 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2A and B). The efficacy we observed is equal to or greater than that observed in other reports using intermittent, high doses of HSP90 inhibitor in this model (24,25). We also found that low-dose Hsp90i administration reduces tumor burden in the MC38 and B16-F10 melanoma model even with delayed administration of low-dose Hsp90i ( Supplementary Fig.…”

Section: Continuous Low-dose Hsp90 Inhibition Stimulates Antitumor Imsupporting

confidence: 70%

“…This finding could have important implications for resistance to immune checkpoint blockade, which can arise following mutational inactivation of IFNg signaling (2,34,35). A recent report describes the induction of a subset of IFN response genes with heat shock-inducing concentrations of HSP90 inhibitor in culture (24). While this report did not directly investigate effects on MHC-I antigen presentation, the results suggest that high level HSP90 inhibition engages IFNg signaling, whereas our data indicate that low dose stimulates antigen presentation through a distinct mechanism.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation

Jaeger

Stopfer

Lee

et al. 2019

Clinical Cancer Research

View full text Add to dashboard Cite

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 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 IFNgindependent 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 nonheat 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.See related commentary

show abstract

Section: Continuous Low-dose Hsp90 Inhibition Stimulates Antitumor Imsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 94%

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation

Jaeger

Stopfer

Lee

et al. 2019

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Nevertheless, although many promising Hsp90 inhibitors have been put on the shelf after extensive preclinical and clinical studies (e.g. 17-AAG, 17-DMAG, AUY922, KW-2478, STA-9090) in the past 20 years, recent studies demonstrated that Hsp90 inhibitors might still be useful for bolstering immunotherapy [11]. Therefore, further studies are needed and Hsp90-survivin inhibitor reposition may be possible, although the effect will likely not be specific to survivin.…”

Section: Inhibitors That Disrupt Survivin Interactions With Its Partnmentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

179

171

View full text Add to dashboard Cite

Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

show abstract

“…Some genes that are known to be directly involved in the MHC I pathway, such as TAP1, TAP2, CALR, TAPBP , and B2M [33], were at the top 1% of our prediction list (Additional file 2: Table S1). Alterations of some top genes in our prediction, such as B2M, JAK1, JAK2, HSP90 , and IFNG , are known to be associated with poor response to anti-PD-1 therapy [7, 33-36]. Several genes that were recently found to be associated with anti-PD-1 response were also identified in the top list of our prediciton, such as KRAS [37], STK11 [38], DDR2 [39], and ATR [40].…”

Section: Resultsmentioning

confidence: 99%

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

Wang

Livingston

et al. 2020

Preprint

View full text Add to dashboard Cite

24 Background: Despite remarkable success, only a subset of cancer patients have shown benefit from the anti-PD1 25 therapy. Therefore, there is a growing need to identify predictive biomarkers and therapeutic combinations for 26 improving the clinical efficacy. 27Results: Based upon the hypothesis that aberrations of any gene that are close to MHC class I genes in the gene 28 network are likely to deregulate MHC I pathway and affect tumor response to anti-PD1, we developed a network 29 approach to infer genes, pathway, and potential therapeutic target genes associated with response to PD-1/PD-L1 30 checkpoint immunotherapies in cancer. Our approach successfully identified genes (e.g. B2M and PTEN) and 31 pathways (e.g. JAK/STAT and WNT) known to be associated with anti-PD1 response. Our prediction was further 32 validated by 5 CRISPR gene sets associated with tumor resistance to cytotoxic T cells. Our results also showed that 33 many cancer genes that act as hubs in the gene network may drive immune evasion through indirectly deregulating 34 the MHC I pathway. The integration analysis of transcriptomic data of the 34 TCGA cancer types and our prediction 35 reveals that MHC I-immunoregulations may be tissue-specific. The signature-based score, the MHC I association 36 immunoscore (MIAS), calculated by integration of our prediction and TCGA melanoma transcriptomic data also 37 showed a good correlation with patient response to anti-PD1 for 354 melanoma samples complied from 5 cohorts. 38In addition, most targets of the 36 compounds that have been tested in clinical trials or used for combination 39 treatments with anti-PD1 are in the top list of our prediction (AUC=0.833). Integration of drug target data with our 40 top prediction further identified compounds that were recently shown to enhance tumor response to anti-PD1, such 41 as inhibitors of GSK3B, CDK, and PTK2. 42Conclusion: Our approach is effective to identify candidate genes and pathways associated with response to anti- 43PD-1 therapy, and can also be employed for in silico screening of potential compounds to enhances the efficacy of 44 anti-PD1 agents against cancer. 45 46 47 48 50 Breakthroughs in cancer immunotherapies have opened a new front in the war against cancer [1]. Instead of 51 directly targeting cancer cells using specific inhibitors, immunotherapies stimulate and modulate the host's 52 immune system to eliminate cancer cells. Recently, immune checkpoint blockade (ICB), which enhances T-cell 53 activity by inhibiting immunosuppressive checkpoint molecules such as cytotoxic T-lymphocyte-associated antigen 54 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death protein ligand 1 (PD-L1), has produced 55remarkably durable responses in some cancer patients. Despite these successes, only a subset of cancer patients 56 benefits from these therapies, and rates of response vary widely among cancer types. Therefore, there is a growing 57 need to understand the mechanisms underlying this de novo resistance, to select predictive biomar...

show abstract

HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes

Cited by 106 publications

References 37 publications

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation

Rebalancing Protein Homeostasis Enhances Tumor Antigen Presentation

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

A computational network approach to identify predictive biomarkers and therapeutic combinations for anti-PD-1 immunotherapy in cancer

Contact Info

Product

Resources

About