ISO: a critical evaluation of the role of peptides in heat shock/chaperone protein-mediated tumor rejection

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Abstract

Heat shock/chaperone protein (HSCP)–peptide complexes can access the cross-priming pathways of antigen presenting cells (APCs), and the gp96-associated peptides can be re-presented on APC MHC class I molecules to elicit CD8+ T cell activation. This immunological circuit is thought to provide the functional basis for HSCP function in tumor immunity. Recent findings identifying a ‘natural adjuvant’ function for HSCPs suggest complementary, or perhaps alternative, mechanisms of HSCP-mediated tumor rejection.

Introduction

The remarkable discovery that immunization of mice with tumor-derived gp96 (also called GRP94) elicits anti-tumor immune responses has fostered the development of an emerging field of study, the immunobiology of heat shock/chaperone proteins (HSCPs), and has also provided promising new immunotherapeutic agents for the treatment of cancer and infectious diseases [1••]. In the basic science community, these observations have prompted the exploration of HSCP function where no function had been previously envisioned, including in the extracellular space, where such proteins reside following pathological cell death 2., 3., the cell surface of antigen presenting cells (APCs), which bear receptors functioning both in receptor-mediated endocytosis of HSCPs 4., 5., 6. and HSCP-dependent activation of cellular signal transduction pathways 2., 7.••, and lastly, the endocytic compartments of APCs, which are accessed by these proteins following clearance from the extracellular space [8]. Given these broad functions, HSCPs are uniquely poised to modify immune cell function and guide immunological responses to foreign pathogens or tumor cells. This review summarizes the current knowledge regarding the role of HSCP-bound peptides in the elicitation of cellular immune responses, provides a critical evaluation of the biochemical evidence for peptide binding as an in vivo function of HSCPs, and discusses recent literature on HSCP interaction with the innate immunity arm of the cellular immune response.

Section snippets

Establishing a molecular mechanism for heat shock/chaperone protein function in tumor rejection

With the passage of time, it has become apparent that HSCPs display a variety of interactions with cells of the immune system, most notably with APCs [1••]. With each new discovery, however, come new questions regarding the mechanism of HSCP function in tumor rejection. The founding experiments in the field, in which gp96 was observed to function as a tumor-specific transplantation antigen (TSTA), were highly influential in guiding the development of models for gp96-mediated tumor rejection [9]

Peptides and proteins as sources of immunogenic activity

A frequently overlooked issue in the study of HSCP immunogenicity is that of protein purity. Protein purification, by nature, is a process that approaches, but very rarely achieves, the goal of absolute purity. Deciding on a standard of purity requires consideration of what the protein will be used for: protein sufficiently pure for one use may contain co-purifying molecules making it unsuitable for another. Arthur Kornberg [19] observed “No enzyme is purified to the point of absolute

Heat shock/chaperone proteins: activators of innate immunity

An additional immunological role for HSCPs has been defined in recent years; HSCPs from both mammalian and microbial sources act as natural adjuvants and thereby elicit cytokine secretion, upregulation of co-stimulatory molecule expression and upregulation of MHC class II expression in APCs 2., 20., 32., 33.. These effects are thought to reflect HSCP-dependent activation of the NF-κB signaling pathways 2., 32.. As a member of the HSCP family, gp96 is known to activate IL-12, TNF-α and IL-1β

Conclusions

The current paradigm for HSCP function in tumor rejection is intuitively appealing and consistent with considerable immunological data. Yet, important questions remain regarding the physiological basis for peptide binding, the identification of an appropriately diverse HSCP-bound peptide pool, and the contribution of bystander proteins to HSCP-elicited immune responses. Recent insights into the interactions of HSCPs with the innate immune system, and the role(s) of innate immunity in tumor

Update

In a recent publication [55••], the binding of radiolabeled peptides to the amino-terminal domain of GRP94 is demonstrated and differences between GRP94 and BiP in preferred peptide substrates are reported. A detailed analyses of peptide VSV8 binding indicated a very high apparent Kd (0.8 millimolar) and a remarkably slow on rate, with saturation requiring a 36 hour incubation at room temperature. Consistent with past studies, peptide binding was irreversible under native conditions.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

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