HSP90 and Immune Modulation in Cancer

doi:10.1016/bs.acr.2015.10.001

Advances in Cancer Research

Volume 129, 2016, Pages 191-224

https://doi.org/10.1016/bs.acr.2015.10.001 Get rights and content

Abstract

Heat-shock protein 90 (HSP90) is a highly conserved molecular chaperone that plays prominent functional roles in nearly all aspects of cell biology. As a chaperone, it interacts with literally hundreds of “clients,” many of which are important drivers, regulators, and promoters of cancer. Thus, HSP90 is a high-value target in the development of anticancer therapeutics. Despite its popularity, our overall knowledge of HSP90 in immune function has lagged behind its well-recognized tumor-supportive roles. The use of inhibitors of HSP90 as chemical biological probes has been invaluable in revealing important roles for the chaperone in multiple aspects of immune function. Given this critical link, we must now consider the question of how immune outcomes may be affected by the HSP90 inhibitors currently in clinical development for the treatment of cancer. This chapter will review some of the immunological aspects of HSP90 function in terms of its intracellular and extracellular roles in antigen presentation, immune effector cell tasks, and regulation of inflammatory processes. This review will further examine the value of HSP90 inhibitors within the context of cancer immunotherapy and will discuss how these drugs might be optimally utilized in combination with immune stimulatory approaches against cancer.

Introduction

Heat-shock protein 90 (HSP90) is one of the most abundant chaperones in the cell, and it is one of the most complex in terms of its protein–protein interactions and overall effects on cellular functions. HSP90 interacts with scores of client proteins, many of which are critical players in tumorigenesis, cancer progression, metastasis, and immune suppression. Thus, the chaperone is a high-value target for pharmacologic inhibitors (Bhat et al., 2014, Jhaveri et al., 2014, Kim et al., 2013, Sidera and Patsavoudi, 2014). Decades of research in tumor immunology have revealed unique properties of the chaperone in the modulation of immune responses in cancer. This review will now examine some of the roles that have emerged for HSP90 in cancer immunology, including effects in tumor cells, immune cells, and activities in the extracellular environment. As we dissect the literature on this topic, we will highlight the complex and multifunctional roles of HSP90 in modulating cancer immunity.

Section snippets

A Brief Primer on Cancer Immunology

Given the complexity of the immune system, select aspects and players relevant to cancer immunology are depicted in Fig. 1 to orient the reader to the essential immune cell types impacted by HSP90 functions.

The mammalian immune system consists of innate and adaptive cell types, with antigen-presenting cells (APCs) forming a conduit between the two sides. The innate responder cells are present to respond to pathogens or insults without need for “education” or “training” as is necessary for the

HSP90 and Its Roles in Immunity (or, How This All Began): HSP90 as an Anticancer Vaccine

From an historical perspective, the initial connections between HSP90 and immune function came about fortuitously, following the “brute force” purification of tumor antigens from murine tumor cells. Almost 30 years ago, Ullrich et al. identified a “tumor-specific transplantation antigen” from chemically induced murine tumors (Meth A) as HSP90, where it appeared to be a cell-surface antigen (Ullrich, Robinson, Law, Willingham, & Appella, 1986). Similarly, Srivastava et al. identified a tumor

Extracellular/Cell Surface HSPs and “Danger Signals”: The Mode of Cell Death Matters to the Immune System

Although HSP90α/β is predominantly cytosolic, HSP90 can also be cell surface localized, usually under pathologic conditions (Cid et al., 2009, Erkeller-Yuksel et al., 1992, Ferrarini et al., 1992, Graner and Bigner, 2006), and also in certain physiological processes such as neuronal migration (Sidera, Samiotaki, Yfanti, Panayotou, & Patsavoudi, 2004). Extracellular release of HSP90 occurs, as well (Hance et al., 2012, Nolan et al., 2015, Suzuki and Kulkarni, 2010), including release via

Extracellular HSP90 in/on Exosomes and the Effects of Heat Stress on HSP90 Immunogenicity

In terms of other forms of extracellular HSP90 (and potentially cancer immunotherapeutics), a version of “extracellular” HSP90 may arise in the form of exosomes. These virus-sized extracellular vesicles are formed in the endosomal pathway as intralumenal vesicles in multivesicular bodies that are released outside the cell (Ung et al., 2014, Yanez-Mo et al., 2015). We have demonstrated the ability of tumor-derived exosomes harboring significant HSP content to function as vaccines (Graner et al.,

…But Is Externalized HSP90 Always an Immune Trigger? The Significance of Nonimmune Roles for Extracellular HSP90

While cell surface and extracellular HSPs are most commonly associated with induction of immune responses (Didelot et al., 2007), it is obvious that surface-localized or extracellularly released HSP90 in situations not involving cell death might also benefit the tumor in some way. One scenario is that noncanonical localization could play a role in modulation of the tumor microenvironment. For instance, extracellular HSP90 appears to chaperone plasminogen and to assist in plasmin generation,

Back Inside the Cell: HSP90 in Antigen Presentation: Are HSP90 Inhibitors a Boon or a Bane?

In the literature describing HSP-based vaccines, chaperones/HSPs in the cytosol and ER are hypothesized to be associated with proteasome-derived peptides and thought to function as a “relay line” to pass the peptides from HSP90 to HSP70, through the TAP into the ER, where GRP94 can finally assist in loading of the peptide onto MHC I molecules (Srivastava, Udono, Blachere, & Li, 1994; depicted in Fig. 3). Other studies have implied that GRP94 may not be essential to priming of MHC I with

Beyond Antigen Presentation: HSP90 in Inflammatory Processes

The state and type of APC may be important when examining the effects of HSP90 inhibitors on immune cell types. To illustrate these potentially complex context-dependent effects, exposure of human monocyte-derived DCs to therapeutically relevant concentrations of GA (0.1 μM) caused partial activation (measured by MHC II and costimulatory markers) of previously unstimulated (e.g., “immature”) DC. However, low-dose GA coadministered with a stimulation cocktail (designed to drive activation)

Treatment of Tumors with HSP90 Inhibitors: A Case for Dose-Dependent Immune Consequences

As described above, the bulk of evidence from cell culture and animal models now indicates (but not unequivocally) that immune responses are reduced by HSP90 inhibition. One might therefore conclude that HSP90 inhibitors as cancer therapeutics would utterly preclude their use in antitumor immune-promoting treatment scenarios, and might even have detrimental effects if antitumor immunity was sufficiently compromised. This could be particularly problematic for cancer patients who are typically in

HSP90 as an Immune Target, as a Drug Target, and at the Intersection of Chemotherapy and Immunotherapy

As discussed near the beginning of this review, HSP90 was first linked to immunity by virtue of its activity as an anticancer vaccine. While that line of research initiated an entire field of chaperone-based cancer immunotherapies, the presumed HSP90–peptide complexes were generally found less effective as anticancer vaccines compared to tumor-derived HSP70, GRP94, or calreticulin (Graner et al., 2000, Udono and Srivastava, 1994). With only a few exceptions since this early work (Corigliano et

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CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.
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Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8⁺ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action.
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Chapter Eight - HSP90 and Immune Modulation in Cancer

Abstract

Introduction

Section snippets

A Brief Primer on Cancer Immunology

HSP90 and Its Roles in Immunity (or, How This All Began): HSP90 as an Anticancer Vaccine

Extracellular/Cell Surface HSPs and “Danger Signals”: The Mode of Cell Death Matters to the Immune System

Extracellular HSP90 in/on Exosomes and the Effects of Heat Stress on HSP90 Immunogenicity

…But Is Externalized HSP90 Always an Immune Trigger? The Significance of Nonimmune Roles for Extracellular HSP90

Back Inside the Cell: HSP90 in Antigen Presentation: Are HSP90 Inhibitors a Boon or a Bane?

Beyond Antigen Presentation: HSP90 in Inflammatory Processes

Treatment of Tumors with HSP90 Inhibitors: A Case for Dose-Dependent Immune Consequences

HSP90 as an Immune Target, as a Drug Target, and at the Intersection of Chemotherapy and Immunotherapy

Cell Stress & Chaperones

Biochemical and Biophysical Research Communications

Cell Stress & Chaperones

Mucosal Immunology

Vaccine

Immunology Letters

The Journal of Biological Chemistry

Blood

Human Immunology

Journal of Autoimmunity

Blood

Blood

Blood

Annals of Oncology

Current Opinion in Immunology

The Journal of Biological Chemistry

Biochemical and Biophysical Research Communications

Seminars in Immunology

Molecular Cell

Immunity

International Review of Cell and Molecular Biology

Molecular Therapy

The Journal of Biological Chemistry

Journal of Immunological Methods

Experimental and Molecular Pathology

Immunobiology

The Journal of Biological Chemistry

Immunity

Current Opinion in Immunology

Trends in Molecular Medicine

Immunology Letters

The Journal of Biological Chemistry

Tumor-intrinsic and tumor-extrinsic factors impacting hsp90- targeted therapy

Current Molecular Medicine

Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell

Journal of Immunology

Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells

Journal of Immunology

Multiple drug resistance mechanisms in cancer

Molecular Biotechnology

Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway

International Immunology

Fever-like temperature induces maturation of dendritic cells through induction of hsp90

International Immunology

Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs

Journal of Leukocyte Biology

Progress in the discovery and development of heat shock protein 90 (Hsp90) inhibitors

Journal of Medicinal Chemistry

Heat shock protein 90 inhibitor BIIB021 (CNF2024) depletes NF-kappaB and sensitizes Hodgkin's lymphoma cells for natural killer cell-mediated cytotoxicity

Clinical Cancer Research

Exosomes from dendritic cells loaded with chaperone-rich cell lysates elicit a potent T cell immune response against intracranial glioma in mice

Journal of Molecular Neuroscience

Heat-shock protein 90 associates with N-terminal extended peptides and is required for direct and indirect antigen presentation

Proceedings of the National Academy of Sciences of the United States of America

Photodynamic therapy and anti-tumour immunity

Nature Reviews. Cancer

Efficient induction of antitumor T cell immunity by exosomes derived from heat-shocked lymphoma cells

European Journal of Immunology

Targeted inhibition of heat shock protein 90 suppresses tumor necrosis factor-alpha and ameliorates murine intestinal inflammation

Inflammatory Bowel Diseases

More efficient induction of HLA-A*0201-restricted and carcinoembryonic antigen (CEA)-specific CTL response by immunization with exosomes prepared from heat-stressed CEA-positive tumor cells

Clinical Cancer Research

Rationale for a multimodality strategy to enhance the efficacy of dendritic cell-based cancer immunotherapy

Frontiers in Immunology

Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells

Molecular and Cellular Biology

Glioblastoma cancer stem cells: Heterogeneity, microenvironment and related therapeutic strategies