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Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models.

ABSTRACT: Tumor-associated antigens (TAAs) include overexpressed self-antigens (for example, Her2/neu) and tumor virus antigens (for example, HPV-16 E6/E7). Although in cancer patients, TAA-specific CD4+ and CD8+ cells are often present, they are not able to control tumor growth. In recent studies, it became apparent that tumor site-located immune evasion mechanisms contribute to this phenomenon and that regulatory T cells have a major role. We tested in Her2/neu+ breast cancer and HPV-16 E6/E7+ cervical cancer mouse models, whether intratumoral expression of immunostimulatory proteins (ISPs), for example, recombinant antibodies (?CTLA-4, ?CD137, ?CD3), cyto/chemokines (IL-15, LIGHT, mda-7) and costimulatory ligands (CD80), through adenovirus(Ad)-mediated gene transfer would overcome resistance. In both the breast and cervical cancer model, none of the Ad.ISP vectors displayed a significant therapeutic effect when compared with an Ad vector that lacked a transgene (Ad.zero). However, the combination of Ad.ISP vectors with systemic T regulatory (Treg) depletion, using anti-CD25?mAb (breast cancer model) or low-dose cyclophosphamide (cervical cancer model) resulted in a significant delay of tumor growth in mice treated with Ad.?CTLA4. In the cervical cancer model, we also demonstrated the induction of a systemic antitumor immune response that was able to delay the growth of distant tumors. Ad.?CTLA4-mediated tumor-destructive immune responses involved NKT and CD8+ T cells. In both models no autoimmune reactions were observed. This study shows that Ad.?CTLA4 in combination with systemic Treg depletion has potentials in the immunotherapy of cancer.

SUBMITTER: Liu Y

PROVIDER: S-EPMC3096725 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models.

Liu Y Y Tuve S S Persson J J Beyer I I Yumul R R Li Z Y ZY Tragoolpua K K Hellström K-E KE Roffler S S Lieber A A

Cancer gene therapy 20110311 6

Tumor-associated antigens (TAAs) include overexpressed self-antigens (for example, Her2/neu) and tumor virus antigens (for example, HPV-16 E6/E7). Although in cancer patients, TAA-specific CD4+ and CD8+ cells are often present, they are not able to control tumor growth. In recent studies, it became apparent that tumor site-located immune evasion mechanisms contribute to this phenomenon and that regulatory T cells have a major role. We tested in Her2/neu+ breast cancer and HPV-16 E6/E7+ cervical ...[more]

PMID: 21394107

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Project description:Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAA), such as chimeric antigen receptor T-cell therapy. We hypothesize that oncolytic adenovirus Delta-24-RGDOX activates the TME and promote antigen spread to potentiate the abscopal effect of adoptive TAA-targeting T cells in localized intratumoral treatment. Herein, we used C57BL/6 mouse models with disseminated tumors derived from B16 melanoma cell lines to assess therapeutic effects and antitumor immunity. gp100-specific pmel-1 or ovalbumin (OVA)-specific OT-I T cells were injected into the first subcutaneous tumor, followed by three injections of Delta-24-RGDOX. We found TAA-targeting T cells injected into one subcutaneous tumor showed tumor tropism. Delta-24-RGDOX sustained the systemic tumor regression mediated by the T cells, leading to improved survival rate. Further analysis revealed that, in mice with disseminated B16-OVA tumors, Delta-24-RGDOX increased CD8+ leukocyte density within treated and untreated tumors. Importantly, Delta-24-RGDOX significantly reduced the immunosuppression of endogenous OVA-specific CTLs while increasing that of CD8+ leukocytes and, to a lesser extent, adoptive pmel-1 T cells. Consequently, Delta-24-RGDOX drastically increased the density of the OVA-specific CTLs in both tumors, and the combination synergistically enhanced the effect. Consistently, the splenocytes from the combination group showed a significantly stronger response against other TAAs (OVA and TRP2) than gp100, resulted in higher activity against tumor cells. Therefore, our data demonstrate that, as an adjuvant therapy followed TAA-targeting T cells in localized treatment, Delta-24-RGDOX activates TME and promotes antigen spread, leading to efficacious systemic antitumor immunity to overcome tumor relapse.SignificanceAdjuvant therapy with oncolytic viruses promotes antigen spread to potentiate localized intratumoral adoptive T-cell therapy with limited TAA targets, leading to sustainable systemic antitumor immunity to overcome tumor relapse.

Dataset Information

Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models.

Publications

Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models.

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