Large stress/heat shock proteins (LSPs) that are complexed in vitro with clinically relevant tumor protein antigens by heat shock have demonstrated highly potent antitumor efficacy in animal models. However, the molecular basis of immunoregulatory features of LSPs remains largely undetermined. Our initial work led to an unexpected finding that enhanced cross-presentation of melanoma protein antigen (Ag) by exogenously delivered LSP involved the endoplasmic reticulum-associated degradation (ERAD) machinery, an intracellular protein quality control system. In addition, for the first time we have discovered that LSPs actively interact with pathogen-derived molecules or PAMPs, resulting in synergistic activation of intracellular NOD-like receptor (NLR)/inflammasome. These observations, which implicate the molecular chaperoning underlying the essential immunologic activities of LSPs, lead us to hypothesize that LSPs are capable of engaging and bridging both innate and adaptive compartments through their highly efficient chaperoning functions. The overall objective of this application is to investigate the highly novel aspects of LSPs in interacting with a self tumor protein Ag and PAMP molecules, as well as distinct immune consequences. Furthermore, LSP-primed cellular responses under physiologically relevant fever-like thermal stress conditions will be assessed. As a consequence of these studies, a novel approach to further enhance the therapeutic potency of the chaperone vaccine regimen by integrating both Ag target and PAMP molecules will be evaluated. The following specific aims will be pursued to achieve the project goal: 1) Determine the protein quality control mechanisms underlying LSP-enhanced cross-presentation of tumor protein Ag. 2) Determine the capability of LSP to interact with PAMPs and modify the resultant immune outcomes. 3) Determine the antitumor efficacy of a modified chaperone vaccine regimen incorporating a PAMP-derived 'danger'signal. Given the common chaperoning property shared by different classes of heat shock proteins, successful completion of these studies will provide important insights into the unique biological activities of these ancient molecules. The proposed studies will also shed new light on the role of mild thermal stress/hyperthermia in the host response, which could be exploited therapeutically for immune modulation. A detailed understanding of the LSP action in host defense mechanisms should provide more effective and safe strategies for targeting cancer and other diseases of clinical importance.

Public Health Relevance

Defining the precise roles of stress proteins in the host response will advance our knowledge on the action mechanisms of chaperone vaccines, and facilitate the development of novel approaches for therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Radiation Therapeutics and Biology Study Section (RTB)
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Welch, Anthony R
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Virginia Commonwealth University
Schools of Medicine
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Guo, Chunqing; Hu, Fanlei; Yi, Huanfa et al. (2014) Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis. Ann Rheum Dis :
Menezes, Mitchell E; Das, Swadesh K; Emdad, Luni et al. (2014) Genetically engineered mice as experimental tools to dissect the critical events in breast cancer. Adv Cancer Res 121:331-82
Wang, Hongxia; Yu, Xiaofei; Guo, Chunqing et al. (2013) Enhanced endoplasmic reticulum entry of tumor antigen is crucial for cross-presentation induced by dendritic cell-targeted vaccination. J Immunol 191:6010-21
Guo, Chunqing; Manjili, Masoud H; Subjeck, John R et al. (2013) Therapeutic cancer vaccines: past, present, and future. Adv Cancer Res 119:421-75
Yu, Xiaofei; Wang, Xiang-Yang (2013) Engineering Grp170-based immune modulators for cancer immunotherapy. Oncoimmunology 2:e24385
Yu, Xiaofei; Subjeck, John R; Wang, Xiang-Yang (2013) Integrating a 'danger' signal into molecular chaperoning to improve vaccination against cancer. Expert Rev Vaccines 12:581-3
Wang, Xiang-Yang; Subjeck, John R (2013) High molecular weight stress proteins: Identification, cloning and utilisation in cancer immunotherapy. Int J Hyperthermia 29:364-75
Yu, Xiaofei; Guo, Chunqing; Yi, Huanfa et al. (2013) A multifunctional chimeric chaperone serves as a novel immune modulator inducing therapeutic antitumor immunity. Cancer Res 73:2093-103
Zuo, Daming; Yu, Xiaofei; Guo, Chunqing et al. (2013) Scavenger receptor A restrains T-cell activation and protects against concanavalin A-induced hepatic injury. Hepatology 57:228-38
Yi, Huanfa; Zuo, Daming; Yu, Xiaofei et al. (2012) Suppression of antigen-specific CD4+ T cell activation by SRA/CD204 through reducing the immunostimulatory capability of antigen-presenting cell. J Mol Med (Berl) 90:413-26

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