Sustained low-level expression of interferon-γ promotes tumor development: potential insights in tumor prevention and tumor immunotherapy

He, Yufei; Wang, Xiaohong; Zhang, Guimei; Chen, Hongtao; Zhang, Hui; Feng, Zuo-Hua

doi:10.1007/s00262-004-0654-1

Cited by 59 publications

(58 citation statements)

References 24 publications

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“…23,24,39 Therefore, the reasons for the paradoxical dissociation between vaccine-induced T-cell responses and the lack of their effectiveness in inducing tumor regression should be sought by complementing the analysis of the systemic effects of vaccines with the simultaneous study of tumor-host interactions at the tumor site. 40 In the present study, the immunization with HSP70 vaccine led to an effective inducement of specific T-cell responses against melanoma antigen, which was indicated by the significant infiltration of T cells into the tumors, a profile of the expression of T H 1 cytokines IFN-g and IL-2, as well as the successful inhibition of B16F1 melanoma in vivo. Nonetheless, HSP70 vaccine-induced tumor-specific T cells did not coincide with tumor clearance, indicating that the residual tumor cells were capable of escaping from immune attack.…”

Section: Discussionmentioning

confidence: 89%

HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD‐1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma

Geng

Zhang

Xiao

et al. 2006

Intl Journal of Cancer

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Many tumor immunotherapy efforts are focused on the generation of strong T-cell response against tumor antigens. However, strong T-cell response does not always coincide with tumor rejection, for which upregulated expression of immunoinhibitory molecules may be responsible. In this study, the treatment with heat shock protein 70 (HSP70) vaccine induced an infiltration of T cells into the tumor site as well as the expression of IFN-c and IL-2, and delayed lung metastases of tumor, but the tumor progression nonetheless occur finally. We demonstrated that B7-H1 expressed by residual tumor cells was responsible for the resistance of tumor to the therapy with HSP70 vaccine. Blockade of B7-H1 by i.v. injection pPD-1A, a plasmid encoding the extracellular domain of PD-1 (sPD-1), could reverse this resistance and enhance the therapeutic efficacy. To complement these findings, we investigated the gene expression of tumor-infiltrating lymphocytes (TILs) by Realtime PCR analysis, which revealed that the expression of T H 1 cytokines IFN-c and IL-2 by TIL in the mice treated with HSP70 vaccine in combination with sPD-1 was increased and the expression of negative regulatory molecules IL-10, TGF-b and foxp3 was decreased, demonstrating that multifunctional properties afforded by the combination therapy can effectively overcome tumor resistance and promote effective antitumor immunity. The in vivo transfection with pPD-1A could be performed as infrequently as once a week and still produce a significant antitumor effect. These findings suggest that the treatment with HSP70 vaccine followed by blockade of tumor-B7-H1 with sPD-1 may provide a promising approach for tumor immunotherapy. ' 2006 Wiley-Liss, Inc.Key words: tumor immunotherapy; tumor immunity; immune escape; gene therapy The molecular hallmark of antigens preferentially expressed by tumor cells has attracted numerous interests in the development of tumor antigen based vaccinations. The ability of heat shock proteins (HSPs) to bind cellular peptides makes them the attractive candidates for cancer vaccines. 1-5 HSPs obtained from tumors or virus-infected cells have been shown to induce CTL responses in vitro and in vivo against a variety of antigens expressed in the cells from which HSPs were purified. The immunogenicity of HSP preparations has been attributed to peptides bound to HSPs. 1 HSPs are able to chaperon antigenic peptides into antigen-presenting cells (APCs) by binding to specific receptor on APCs. 6-9 The binding of HSP-peptide complex to APCs triggers a cascade of events, including re-presentation of the chaperoned peptides by the major histocompatibility complex, secretion of proinflammatory cytokines and maturation of DCs. 10-12 These properties make HSPs-based vaccination a powerful therapeutic approach to produce tumor antigen specific T cells.Besides HSPs-based vaccination, many current attempts at harnessing the immune system are capable of eliciting strong T-cell responses against tumor antigens, as high frequencies of tumor antigen specific T cell...

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Section: Discussionmentioning

confidence: 89%

HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD‐1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma

Geng

Zhang

Xiao

et al. 2006

Intl Journal of Cancer

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“…This is because of the tumor microenvironment effect on immune cells and evasion mechanisms employed by tumors (Blank et al 2004;Curier et al 2004;Hirano et al 2005). Hence, the lack of vaccine effectiveness should be analyzed locally and systemically, i.e., systemic effect of vaccine and the tumor-host mutual talk at the tumor foci (He et al 2005).…”

Section: Discussionmentioning

confidence: 99%

N-terminally fusion of Her2/neu to HSP70 decreases efficiency of Her2/neu DNA vaccine

Pakravan

Soudi

Hassan

2010

Cell Stress and Chaperones

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DNA vaccines consisted of tumor-associated antigen (TAA) are well suited for immunotherapy against tumor. The construct can contain TAA fused to an appropriate molecule (biologic adjuvant) to improve the efficacy of anti-tumor immune response. Heat shock protein 70 (HSP70) has been shown to be an excellent candidate, capable of cross-priming TAA by antigen presenting cells leading to a robust T-cell response. However, the relationship between strong T-cell responses and tumor rejection is not always mutually exclusive, for which TAA loss or activation of suppressive mechanisms may occur. HSP70 fused to downstream of Her2/neu as DNA vaccine has been shown to be efficient against Her2-expressing tumors. In this study, we examined if N-terminally fusion of Her2/neu to HSP70 could also improve efficiency of Her2/neu DNA vaccine. Therefore, mice with an established Her2/neu expressing tumor were immunized with DNA vaccine consisting of extracellular and trans-membrane domain (EC+TM) of rat Her2/neu alone or N-terminally fused to HSP70 and immune response was evaluated. Administration of rat Her2/neu led to partial control of tumor progression. Surprisingly, fusion of HSP70 to N-terminal of rat Her2/neu led to tumor progression. Our result proposes that fusion direction of biologic adjuvant is an important consideration when Her2/neu is used.

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“…[6][7][8][9] Although IFN-g has also been found to promote tumor immune evasion by downregulating cellular level of an endogenous tumor antigen 10 and induce the negative immune regulation by upregulating B7-H1 expression, 11,12 the increase of IFN-g level is still crucial for the therapeutic efficacy of different immunotherapeutic approaches. However, despite the extensive studies on the positive and negative effects of IFN-g on tumor growth, little is known about the influence of IFN-g on the metastatic behavior of tumor cells.…”

Section: Abstract: Immunotherapy; Tumor Metastasis; Interferon C; Inmentioning

confidence: 99%

“…11,12 The in vivo transfection was performed by direct local injection or using the hydrodynamics-based gene-delivery technique. Briefly, naked plasmid (100 lg in 100 lL of saline) was injected directly into the muscle (i.m.…”

Section: In Vivo Gene Transfectionmentioning

confidence: 99%

IFN‐γ withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin αvβ3 signaling

Gong

Zhang

Liu

et al. 2008

Intl Journal of Cancer

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Immunotherapy can effectively suppress tumor, yet complete tumor eradication occurs infrequently. The metastatic potential of remnant tumor cells after immunotherapy and the underlying mechanisms have not been fully elucidated. Here, we report that the termination of immunotherapy strikingly increases the metastatic potential of remnant melanoma. This is mainly due to the withdrawal of IFN-c after immunotherapy. The relief of IFN-c stress led to the increase of avb3 integrin expression in B16 cells, which increased the adhesion of B16 cells to fibrinogen, fibronectin and laminin. Through avb3 signaling, the activation of FAK, upregulation of cdc2, production of active MMP-2 and MMP-9 and actin polymerization were intensified in B16 cells stimulated with ECM molecules 24 h after the withdrawal of IFN-c. The i.v. injection of such tumor cells into mice resulted in more metastatic tumor nodes in lung and shortened the survival of mice. The pitfall of immunotherapy termination can be remedied by the administration of recombinant CBD-HepII polypeptide of fibronectin, which effectively inhibits avb3 signaling. These findings suggest that the risk of tumor metastasis can be increased after the termination of immunotherapy, due to the withdrawal of IFN-c and that targeting avb3 signaling pathway can improve the therapeutic effect of immunotherapeutic approaches by reducing such metastatic risk. ' 2008 Wiley-Liss, Inc. Key words: immunotherapy; tumor metastasis; interferon c; integrin avb3Progress in molecular and cellular immunology during the past two decades has advanced our understanding of tumor-host interactions and opened extraordinary opportunities for the development of antitumor immunotherapy. 1 So far, there are many available approaches designed to modulate the immune system for a better efficacy in tumor immunotherapy. Although the exciting efficacy has been obtained by using these approaches, the complete tumor eradication occurs infrequently. Tumor recurrence and metastasis are frequently the final and fatal step in the progression of solid malignancies in patients after immunotherapy. It has been found that a variety of molecular alterations occur in tumors so that they become more progressive and better equipped to evade or inhibit host defenses. 2-5 However, it is still unclear which factor(s) is responsible for the inhibition of tumor metastasis during immunotherapy and what happens if such factor(s) is downregulated after immunotherapy.Interferon g (IFN-g) is an important cytokine produced by the activated lymphocytes and contributes to antitumor activity via several mechanisms, including phenotypic or functional modification of neoplastic cells, rendering them more amenable to immune recognition and attack via Fas-dependent and Fas-independent pathways. 6-9 Although IFN-g has also been found to promote tumor immune evasion by downregulating cellular level of an endogenous tumor antigen 10 and induce the negative immune regulation by upregulating B7-H1 expression, 11,12 the increase of IFN-g level is...

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Sustained low-level expression of interferon-γ promotes tumor development: potential insights in tumor prevention and tumor immunotherapy

Cited by 59 publications

References 24 publications

HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD‐1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma

HSP70 vaccine in combination with gene therapy with plasmid DNA encoding sPD‐1 overcomes immune resistance and suppresses the progression of pulmonary metastatic melanoma

N-terminally fusion of Her2/neu to HSP70 decreases efficiency of Her2/neu DNA vaccine

IFN‐γ withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin αvβ3 signaling

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