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Flt3L and GM-CSF enhance anti-tumor effect of HPV16/18 vaccine via increasing immune response.

ABSTRACT: OBJECTIVES:Cervical cancer is the second leading cause of cancer death in women, which is closely related to persistent infection with high-risk Human papillomavirus (HPV). Therefore, it is important to develop new adjuvants for HPV vaccines. This research aimed to establish two new adjuvants which can enhance the immune effect of vaccines. MATERIALS AND METHODS:C57BL/6 mice were divided into 5 groups and immunized by intramuscular injection of plasmid once every 2 weeks, three times in all. The growth and metastasis of tumors in mice was observed by in vivo imaging system (IVIS). Then, the mice were sacrificed and the pathological changes of organs were observed. In addition, the lymphocyte suspension was used for CLT killing test. IFN-? level and the number of splenocytes which secrete IFN-? were detected. Additionally, the specific antibody level of HPV16/18 E6 E7 L1 L2 was also detected. RESULTS:The constructed nucleic acid vaccines had no significant effect on both the physiological and biochemical indexes, while it significantly increased the survival period and survival rate of mice. Flt3L and GM-CSF enhanced the immune effect of HPV16/18 vaccine via increasing the specific antibodies and IFN-? cytokines. CONCLUSIONS:These data suggested that Flt3L and GM-CSF enhanced the anti-tumor effect of vaccines via increasing immune response. Thereby, our findings may hope to provide new perspective for the treatment of cervical cancer.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7653621 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Flt3L and GM-CSF enhance anti-tumor effect of HPV16/18 vaccine via increasing immune response.

Liu Yu Y Zhu Haiyan H Mo Laiming L Xu Rui R Li Xiangyun X Li Tian T Zhao Liang L Ren Yi Y Ou Rongying R Xu Yunsheng Y

American journal of translational research 20201015 10

<h4>Objectives</h4>Cervical cancer is the second leading cause of cancer death in women, which is closely related to persistent infection with high-risk Human papillomavirus (HPV). Therefore, it is important to develop new adjuvants for HPV vaccines. This research aimed to establish two new adjuvants which can enhance the immune effect of vaccines.<h4>Materials and methods</h4>C57BL/6 mice were divided into 5 groups and immunized by intramuscular injection of plasmid once every 2 weeks, three ti ...[more]

PMID: 33194012

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Project description:Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T-cell activation. A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as program death-1 (PD-1/PD-L1) pathway in the tumor environment. However, the determinants of response to anti-PD-1 monoclonal antibodies (mAbs) treatment remain incompletely understood. In murine models, PD-1 blockade alone fails to induce effective immune responses to poorly immunogenic tumors, but is successful when combined with additional interventions, such as cancer vaccines. Novel cancer vaccines combined with antibody may offer promising control of cancer development and progression. In this investigation, we generated a novel tumor cell vaccine simultaneously expressing anti-PD-1 mAbs and granulocyte-macrophage colony stimulating factor (GM-CSF) in CT26 colon cancer and B16-F10 melanoma. The antitumor effect of the vaccine was verified by therapeutic and adoptive animal experiments in vivo. The antitumor mechanism was analyzed using Flow cytometry, Elispot and in vivo intervention approaches. The results showed that tumor cell vaccine secreting PD-1 neutralizing antibodies and GM-CSF induced remarkable antitumor immune effects and prolonged the survival of tumor-bearing animals compared with animals treated with either PD-1 mAbs or GM-CSF alone. Antitumor effects and prolonged survival correlated with strong antigen-specific T-cell responses by analyzing CD11c+CD86+ DC, CD11b+F4/80+ MΦ cells, increased ratio of Teff/Treg in the tumor microenvironment, and higher secretion levels of Th1 proinflammatory cytokines in serum. Furthermore, the results of ELISPOT and in vivo blocking strategies further confirmed that the antitumor immune response is acquired by CD4 and CD8 T immune responses, primarily dependent on CD4 Th1 immune response, not NK innate immune response. The combination of PD-1 blockade with GM-CSF secretion potency creates a novel tumor cell vaccine immunotherapy, affording significantly improved antitumor responses by releasing the state of immunosuppressive microenvironment and augmenting the tumor-reactive T-cell responses.

Project description:BackgroundAlthough the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival.MethodsThe Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy.ResultsThe studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4+ IFN-γ+, CD8+ IFN-γ+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes.ConclusionsThese results provide a new insight into therapeutic mechanisms of IL-18 plus GM-CSF modified tumor cell vaccine and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.

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Flt3L and GM-CSF enhance anti-tumor effect of HPV16/18 vaccine via increasing immune response.

Publications

Flt3L and GM-CSF enhance anti-tumor effect of HPV16/18 vaccine via increasing immune response.

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