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Roles, Mechanisms, and Opportunities of Heat Shock Protein gp96/grp94 in Infections and Inflammation-Associated Malignancies

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Heat Shock Proteins in the Immune System

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Abstract

Heat shock proteins (HSP) gp96 (grp94) play an important role in modulating innate and T cell immunity via interaction with toll-like receptors (TLRs) and chaperoning antigenic peptides for antigen presentation to MHC molecules. These immunological properties of gp96 have inspired development of gp96-based prophylactic and therapeutic vaccines against various pathogens, including influenza virus, human papillomavirus, Mycobacterium tuberculosis, hepatitis B virus, and herpes simplex virus in mice models. Besides the already known underlying counterback mechanisms, the intrinsic characteristic of gp96 that simultaneously induce both effector T cell response and regulatory T cells (Tregs) may account for the modest efficiency of gp96-based immunotherapy against chronic infections and cancer. There is thus a strong need for identifying novel combination strategies (e.g., Treg inhibition, and immune checkpoint targeting) for designing a more effective gp96-based vaccine against pathogen infections. In addition, targeting cell membrane gp96 might provide a novel therapeutic approach as certain pathogens induce translocation of endoplasmic reticulum-resided gp96 to cell surface. Placenta-derived gp96 has the ability to initiate antitumor T-cell immunity via association with multiple embryo-cancer antigens against chronic infection-associated cancers. Further understanding of the placental gp96 associated-carcinoembryonic antigen repertoires that orchestrate immune defense networks against pathogen-induced cancer formation may allow ample opportunities to provide an effective strategy in cancer prevention and therapy.

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Abbreviations

ALT:

Alanine aminotransaminase

APC:

Antigen-presenting cell

BCG:

Bacillus Calmette-Guerin

Con A:

Concanavalin A

CTL:

Cytotoxic T lymphocyte

CTLA4:

Cytotoxic T lymphocyte-associated antigen-4

DC:

Dendritic cell

DENA:

Diethylnitrosamine

Foxp3:

Forkhead/winged helix transcription factor

hbcag:

Hepatitis B core antigen

hbsag:

Hepatitis B surface antigen

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HPV:

Human papillomavirus

HSP:

Heat shock protein

HSV:

Herpes simplex virus

IL:

Interleukin

LPS:

Lipopolysaccharide

mab:

Monoclonal antibody

MHC:

Major histocompatibility complex

MDP:

Muramyl dipeptide

MAPK:

Mitogen-activated protein kinase

NLRP3:

NLR family, pyrin domain containing 3

PD-1:

Programmed death-1

PD-L1:

Programmed death 1 ligand 1

TAP:

Transporter associated with antigen processing

TB:

Tuberculosis

TLR:

Toll like receptor

TNF:

Tumor necrosis factor

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Authors and Affiliations

  1. Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China

    Songdong Meng

  2. Hollings Cancer Center, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    Zihai Li

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  1. Songdong Meng
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  2. Zihai Li
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Correspondence to Songdong Meng .

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Editors and Affiliations

  1. Department of Immunology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA

    Robert J. Binder

  2. Carole and Ray Neag Comprehensive Cancer Center and the Department of Immunology, University of Connecticut School of Medicine, Farmington, Connecticut, USA

    Pramod K. Srivastava

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Meng, S., Li, Z. (2018). Roles, Mechanisms, and Opportunities of Heat Shock Protein gp96/grp94 in Infections and Inflammation-Associated Malignancies. In: Binder, R., Srivastava, P. (eds) Heat Shock Proteins in the Immune System. Springer, Cham. https://doi.org/10.1007/978-3-319-69042-1_7

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