CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC

Nguyen-Hoai, Tam; Hohn, Oliver; Vu, Minh Diem; Baldenhofer, Gerd; Ahmed, Mohamed S. Mohamed; Dörken, Bernd; Norley, Steve; Lipp, Martin; Pezzutto, Antonio; Westermann, Jörg

doi:10.1038/cgt.2012.78

Cited by 27 publications

(19 citation statements)

References 57 publications

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“…Among various means of improving vaccine efficacy, the adoption of adjuvants to promote Ag immunogenicity is one of the simple, yet most effective, ways (5,12). CCL19 was shown to potentiate both cellular and humoral responses to immunogens in mice (16,49), representing a promising molecular adjuvant. In the current study, we designed and evaluated a novel HSV-2 gB-CCL19 fusion construct using CCL19 as the adjuvant, showing that immunization with the fusion constructs enhanced Ag-specific systemic and mucosal Ab responses, as well as balanced Th1/Th2 cellular responses.…”

Section: Discussionmentioning

confidence: 99%

Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

Yan

Deng

et al. 2015

The Journal of Immunology

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There is a lack of an HSV-2 vaccine, in part as the result of various factors that limit robust and long-term memory immune responses at the mucosal portals of viral entry. We previously demonstrated that chemokine CCL19 augmented mucosal and systemic immune responses to HIV-1 envelope glycoprotein. Whether such enhanced immunity can protect animals against virus infection remains to be addressed. We hypothesized that using CCL19 in a fusion form to direct an immunogen to responsive immunocytes might have an advantage over CCL19 being used in combination with an immunogen. We designed two fusion constructs, plasmid (p)gBIZCCL19 and pCCL19IZgB, by fusing CCL19 to the C- or N-terminal end of the extracellular HSV-2 glycoprotein B (gB) with a linker containing two (Gly4Ser)2 repeats and a GCN4-based isoleucine zipper motif for self-oligomerization. Following immunization in mice, pgBIZCCL19 and pCCL19IZgB induced strong gB-specific IgG and IgA in sera and vaginal fluids. The enhanced systemic and mucosal Abs showed increased neutralizing activity against HSV-2 in vitro. Measurement of gB-specific cytokines demonstrated that gB-CCL19 fusion constructs induced balanced Th1 and Th2 cellular immune responses. Moreover, mice vaccinated with fusion constructs were well protected from intravaginal lethal challenge with HSV-2. Compared with pgB and pCCL19 coimmunization, fusion constructs increased mucosal surface IgA+ cells, as well as CCL19-responsive immunocytes in spleen and mesenteric lymph nodes. Our findings indicate that enhanced humoral and cellular immune responses can be achieved by immunization with an immunogen fused to a chemokine, providing information for the design of vaccines against mucosal infection by HSV-2 and other sexually transmitted viruses.

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Section: Discussionmentioning

confidence: 99%

Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

Yan

Deng

et al. 2015

The Journal of Immunology

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“…CCL19 has a more complex role in breast cancer, being used successfully as an adjuvant in cancer vaccines [62,63] but also is implicated in lymphogenous tumor metastasis [8]. Cassier et al .…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, the presence of infiltrating CCL19-expressing DC correlated with an increased risk of relapse which may implicate CCL19 in metastasis via the lymphatic vessels [8]. However, when administered exogenously both intratumorally or intradermally alongside a Her2/neu DNA plasmid vaccine, CCL19 was able to elicit a Th1 anti-tumor response in a mouse model of Her2/neu positive breast cancer [62,63]. 47 days post-tumor xenograft injection, 58% of mice given CCL19 and the Her2/neu adjuvant vaccine were still alive compared to only 22% of mice given the Her2/neu plasmid vaccine alone [62].…”

Section: Introductionmentioning

confidence: 99%

Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

Pimenta

Barnes

2014

Cancers

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Following the successes of monoclonal antibody immunotherapies (trastuzumab (Herceptin®) and rituximab (Rituxan®)) and the first approved cancer vaccine, Provenge® (sipuleucel-T), investigations into the immune system and how it can be modified by a tumor has become an exciting and promising new field of cancer research. Dozens of clinical trials for new antibodies, cancer and adjuvant vaccines, and autologous T and dendritic cell transfers are ongoing in hopes of identifying ways to re-awaken the immune system and force an anti-tumor response. To date, however, few consistent, reproducible, or clinically-relevant effects have been shown using vaccine or autologous cell transfers due in part to the fact that the immunosuppressive mechanisms of the tumor have not been overcome. Much of the research focus has been on re-activating or priming cytotoxic T cells to recognize tumor, in some cases completely disregarding the potential roles that B cells play in immune surveillance or how a solid tumor should be treated to maximize immunogenicity. Here, we will summarize what is currently known about the induction or evasion of humoral immunity via tumor-induced cytokine/chemokine expression and how formation of tertiary lymphoid structures (TLS) within the tumor microenvironment may be used to enhance immunotherapy response.

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“…The images were captured at ×20 objective magnification There are other modalities which could improve the DNA vaccination for tumor regression. For example, application of immunoregulatory chemokines such as CCL19 or CLL21 as adjuvant has been reported to improve tumor eradication by HER2 DNA vaccine in several tumor models [47][48][49]. Another example is the combination of active immunization with HER2 DNA together with passive immunotherapy using HER2-specific mAb which has shown a positive effect in tumor regression in a mouse breast cancer model [31].…”

Section: Discussionmentioning

confidence: 96%

Antibody response to HER2 extracellular domain and subdomains in mouse following DNA immunization

et al. 2015

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Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-20 % of breast cancer patients and is an appropriate target for immunotherapy in these patients. Monoclonal antibodies (mAbs) specific to HER2 are currently applied to treat breast cancer patients with HER2 overexpression. Active immunization with HER2 DNA or protein has been considered as a suitable alternative. The aim of this study is to evaluate anti-HER2 antibody response in serum of mice immunized with DNA constructs containing full extracellular domain (fECD) or subdomains of human HER2. Four extracellular subdomains and also fECD of HER2 were cloned into pCMV6-Neo vector. Different groups of Balb/C mice were immunized with HER2 DNA constructs and boosted with HER2 recombinant protein. The anti-HER2 antibody was subsequently determined by ELISA, flow cytometry, and immunohistochemistry. Anti-HER2 antibody was detected only in serum of mice immunized with fECD DNA. None of HER2 extracellular subdomains induced appreciable levels of anti-HER2 antibody. However, boosting with fECD or extracellular subdomain III (DIII) recombinant protein resulted in enhanced anti-HER2 fECD as well as anti-HER2 subdomain antibody responses. In this regard, almost all (99 %) of HER2-overexpressing BT474 cells could be detected by serum antibody from mice immunized with HER2 subdomain DNA and boosted with recombinant HER2 protein by flow cytometry. Similarly, serum of mice immunized with DIII DNA construct and boosted with recombinant DIII protein could also recognize these cells, but to a lesser extent (50 %). Our findings suggest that combination of HER2 DNA and protein immunization could effectively induce anti-HER2 antibody response in Balb/C mice.

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CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC

Cited by 27 publications

References 57 publications

Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

Immunization with HSV-2 gB-CCL19 Fusion Constructs Protects Mice against Lethal Vaginal Challenge

Role of Tertiary Lymphoid Structures (TLS) in Anti-Tumor Immunity: Potential Tumor-Induced Cytokines/Chemokines that Regulate TLS Formation in Epithelial-Derived Cancers

Antibody response to HER2 extracellular domain and subdomains in mouse following DNA immunization

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