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Engineering Grp170-based immune modulators for cancer immunotherapy.

Yu X, Wang XY - Oncoimmunology (2013)

Bottom Line: We have recently demonstrated that glucose-regulated protein 170 (Grp170), a stress-responsive molecular chaperone of the endoplasmic reticulum, can be exploited to stimulate anticancer immunity due to its superior antigen chaperoning and delivering capacity.The immune remodeling of the tumor microenvironment induced by a Grp170-based chaperone leads to immune responses that effectively control the progression of both primary neoplasms and their metastases.Our findings support the development of Grp170-based immunomodulating strategies to potentiate antitumor immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Human and Molecular Genetics; Virginia Commonwealth University School of Medicine; Richmond, VA USA ; VCU Institute of Molecular Medicine; Virginia Commonwealth University School of Medicine; Richmond, VA USA ; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA.

ABSTRACT
We have recently demonstrated that glucose-regulated protein 170 (Grp170), a stress-responsive molecular chaperone of the endoplasmic reticulum, can be exploited to stimulate anticancer immunity due to its superior antigen chaperoning and delivering capacity. The immune remodeling of the tumor microenvironment induced by a Grp170-based chaperone leads to immune responses that effectively control the progression of both primary neoplasms and their metastases. Our findings support the development of Grp170-based immunomodulating strategies to potentiate antitumor immune responses.

No MeSH data available.


Related in: MedlinePlus

Figure 1. The immunomodulating effects of a multifunctional chimeric chaperone in the tumor microenvironment. Flagrp170 produced by tumor cells delivers tumor-associated antigens to antigen-presenting cells (e.g., DCs) for efficient cross-presentation and T-cell priming. The NFκB signaling pathway is triggered in DCs upon infection with Flagrp170-encoding adenoviruses as well as by extracellular Flagrp170, resulting in their functional activation. The upregulation of co-stimulatory molecules and the production of inflammatory cytokines (e.g., interleukin-12, IL-12) promote the effector functions of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). These cells, possibly via interferon γ (IFNγ) and granzyme B, kill malignant cells, hence causing the release of Flagrp170-tumor antigen complexes that may further amplify T-cell antitumor responses.
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Figure 1: Figure 1. The immunomodulating effects of a multifunctional chimeric chaperone in the tumor microenvironment. Flagrp170 produced by tumor cells delivers tumor-associated antigens to antigen-presenting cells (e.g., DCs) for efficient cross-presentation and T-cell priming. The NFκB signaling pathway is triggered in DCs upon infection with Flagrp170-encoding adenoviruses as well as by extracellular Flagrp170, resulting in their functional activation. The upregulation of co-stimulatory molecules and the production of inflammatory cytokines (e.g., interleukin-12, IL-12) promote the effector functions of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). These cells, possibly via interferon γ (IFNγ) and granzyme B, kill malignant cells, hence causing the release of Flagrp170-tumor antigen complexes that may further amplify T-cell antitumor responses.

Mentions: Our studies provide some insights into the therapeutic effects of Flagrp170. However, further investigation is needed to elucidate the precise molecular and cellular mechanisms that underlie the TME-remodeling activity of Flagrp170 (Fig. 1). Although chronic inflammation has been linked to tumor progression, our findings suggest that appropriately altering the inflammatory properties of the TME may significantly potentiate antitumor immune responses. As Flagrp170 selectively stimulates the NFκB signaling pathway in DCs but not in tumor cells, the therapeutic manipulation of inflammatory responses in the immune compartment of tumors may be essential to break immune tolerance.


Engineering Grp170-based immune modulators for cancer immunotherapy.

Yu X, Wang XY - Oncoimmunology (2013)

Figure 1. The immunomodulating effects of a multifunctional chimeric chaperone in the tumor microenvironment. Flagrp170 produced by tumor cells delivers tumor-associated antigens to antigen-presenting cells (e.g., DCs) for efficient cross-presentation and T-cell priming. The NFκB signaling pathway is triggered in DCs upon infection with Flagrp170-encoding adenoviruses as well as by extracellular Flagrp170, resulting in their functional activation. The upregulation of co-stimulatory molecules and the production of inflammatory cytokines (e.g., interleukin-12, IL-12) promote the effector functions of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). These cells, possibly via interferon γ (IFNγ) and granzyme B, kill malignant cells, hence causing the release of Flagrp170-tumor antigen complexes that may further amplify T-cell antitumor responses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3716734&req=5

Figure 1: Figure 1. The immunomodulating effects of a multifunctional chimeric chaperone in the tumor microenvironment. Flagrp170 produced by tumor cells delivers tumor-associated antigens to antigen-presenting cells (e.g., DCs) for efficient cross-presentation and T-cell priming. The NFκB signaling pathway is triggered in DCs upon infection with Flagrp170-encoding adenoviruses as well as by extracellular Flagrp170, resulting in their functional activation. The upregulation of co-stimulatory molecules and the production of inflammatory cytokines (e.g., interleukin-12, IL-12) promote the effector functions of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). These cells, possibly via interferon γ (IFNγ) and granzyme B, kill malignant cells, hence causing the release of Flagrp170-tumor antigen complexes that may further amplify T-cell antitumor responses.
Mentions: Our studies provide some insights into the therapeutic effects of Flagrp170. However, further investigation is needed to elucidate the precise molecular and cellular mechanisms that underlie the TME-remodeling activity of Flagrp170 (Fig. 1). Although chronic inflammation has been linked to tumor progression, our findings suggest that appropriately altering the inflammatory properties of the TME may significantly potentiate antitumor immune responses. As Flagrp170 selectively stimulates the NFκB signaling pathway in DCs but not in tumor cells, the therapeutic manipulation of inflammatory responses in the immune compartment of tumors may be essential to break immune tolerance.

Bottom Line: We have recently demonstrated that glucose-regulated protein 170 (Grp170), a stress-responsive molecular chaperone of the endoplasmic reticulum, can be exploited to stimulate anticancer immunity due to its superior antigen chaperoning and delivering capacity.The immune remodeling of the tumor microenvironment induced by a Grp170-based chaperone leads to immune responses that effectively control the progression of both primary neoplasms and their metastases.Our findings support the development of Grp170-based immunomodulating strategies to potentiate antitumor immune responses.

View Article: PubMed Central - PubMed

Affiliation: Department of Human and Molecular Genetics; Virginia Commonwealth University School of Medicine; Richmond, VA USA ; VCU Institute of Molecular Medicine; Virginia Commonwealth University School of Medicine; Richmond, VA USA ; VCU Massey Cancer Center; Virginia Commonwealth University School of Medicine; Richmond, VA USA.

ABSTRACT
We have recently demonstrated that glucose-regulated protein 170 (Grp170), a stress-responsive molecular chaperone of the endoplasmic reticulum, can be exploited to stimulate anticancer immunity due to its superior antigen chaperoning and delivering capacity. The immune remodeling of the tumor microenvironment induced by a Grp170-based chaperone leads to immune responses that effectively control the progression of both primary neoplasms and their metastases. Our findings support the development of Grp170-based immunomodulating strategies to potentiate antitumor immune responses.

No MeSH data available.


Related in: MedlinePlus