Elsevier

Vaccine

Volume 26, Issue 46, 29 October 2008, Pages 5855-5863
Vaccine

α-Galactosylceramide enhances the protective and therapeutic effects of tumor cell based vaccines for ovarian tumors

https://doi.org/10.1016/j.vaccine.2008.08.027Get rights and content

Abstract

Ovarian cancer is one of the leading causes of death from gynecological cancers in the United States. Conventional therapies are unlikely to control advanced stage ovarian cancers, thus requiring innovative alternative therapies. In the current study, we characterized the therapeutic effect of tumor cell-based vaccines combined with the adjuvant, α-galactosylceramide (α-GalCer) using two different mouse models. Our data suggests that treatment with α-GalCer led to an increase in the IFN-γ serum levels in the presence or absence of irradiated mouse ovarian surface epithelial tumor cells (MOSEC). Furthermore, administration of irradiated MOSEC tumor cells with adjuvant α-GalCer generated significant protective and therapeutic antitumor effects against MOSEC tumors in vaccinated C57BL/6 mice. In addition, immune cells expressing CD4, CD8 or NK1.1 markers were found to be important for the protective antitumor effects generated by irradiated tumor cell-based vaccines combined with adjuvant α-GalCer. We also found that treatment of a spontaneous ovarian cancer murine model, the Müllerian inhibiting substance type II receptor T antigen (TgMISIIR-TAg) transgenic mice with ovarian tumor cell-based vaccines combined with adjuvant α-GalCer led to prolonged survival as well as increased numbers of tumor-specific CD8+ T cells. Therefore, irradiated tumor cell-based vaccines in combination with α-GalCer are capable of breaking immune tolerance and generating significant antitumor effects in two different mouse tumor models. Our study serves as a foundation for future clinical translation.

Introduction

Ovarian cancer is the sixth most common malignancy in women and the leading cause of death from all gynecological cancers in the United States [1]. Current therapies such as surgery, chemotherapy and radiotherapy usually fail to control advanced stages of the disease. Therefore, alternative approaches such as immunotherapeutic strategies to enhance immune responses may serve as an important method to control these intraperitoneal tumors.

Tumor cell-based vaccines have emerged as an attractive immunological approach for the treatment of ovarian cancer (for review, see [2], [3]). This vaccination strategy has an advantage over other strategies because the irradiated tumor cells are engineered to generate specific immune responses against tumor without the need to identify a specific immunodominant tumor-specific antigenic epitope tumor antigen. However, the efficacy of this approach relies on the ability of the vaccine to effectively induce specific immunity against tumors. Furthermore, multiple antigens relevant to the tumor can be targeted by tumor cell-based vaccines. However, unmodified tumor cell-based vaccines face limitations in their immunogenicity. This has led to the administration of adjuvants, such as cytokines or co-stimulatory molecules, along with tumor cell-based vaccines in order to enhance vaccine potency (for reviews, see [4], [5]). Therefore, strategies to enhance the efficiency of tumor cell-based vaccines such as the use of adjuvants are important for improving the treatment of ovarian tumors.

The glycosphingolipid, α-galactosylceramide (α-GalCer) represents a potential adjuvant for cancer immunotherapy using tumor cell-based vaccines. These molecules have been reported to induce significant antitumor immunity in mouse metastases models [6], [7]. α-GalCer can be presented by CD1d molecules of antigen-presenting cells, and is known to induce a potent natural killer T (NKT) cell-dependent cytotoxic response against tumor cells [8], [9], [10]. α-GalCer has also been shown to enhance the antitumor activity in mice when administered in combination with various types of vaccines [11], [12], [13], [14], [15]. Thus, α-GalCer represents a potential adjuvant for tumor cell-based vaccines.

In the current study, we hypothesized that irradiated tumor cell-based vaccine co-administered with α-GalCer may generate potent antitumor effects against ovarian cancer in vaccinated mice. We have employed a transplantable mouse ovarian surface epithelial carcinoma (MOSEC) model as well as a murine Müllerian inhibiting substance type II receptor T antigen (TgMISIIR-TAg) transgenic mouse model that is capable of developing ovarian cancer spontaneously. We found that treatment with α-GalCer leads to an increase in the IFN-γ serum levels in the presence or absence of irradiated MOSEC tumor cells. Furthermore, administration of irradiated MOSEC tumor cells with adjuvant α-GalCer generated significant protective and therapeutic antitumor effects against MOSEC tumors in vaccinated mice. We also found that treatment of the TgMISIIR-TAg transgenic mice with ovarian tumor cell-based vaccines combined with adjuvant α-GalCer led to prolonged survival as well as increased numbers of tumor-specific CD8+ T cells. Thus, α-GalCer represents an important adjuvant for improving the efficacy of tumor cell-based vaccines to treat ovarian cancer.

Section snippets

Mice and cell lines

Female C57BL/6 mice aged 5–7 weeks were purchased from the National Cancer Institute. Female TgMISIIR-TAg transgenic mice were obtained by breeding female C57BL/6 mice with male TgMISIIR-TAg transgenic mice and used at 6 weeks of age in the experiments. These mice spontaneously developed ovarian tumors with complete tissue penetration. The male MISIIR-TAg transgenic mice were obtained from Fox Chase Cancer Center (Philadelphia, PA, USA) [16]. All animals were maintained under specific

Treatment with α-GalCer leads to an increase in the IFN-γ serum levels in the presence or absence of irradiated MOSEC tumor cells

It has been established that NKT cells quickly respond to α-Galactosylceramide (α-GalCer) by IFN-γ production [20]. In order to determine if administration of α-GalCer will lead to IFG-γ secretion in vaccinated mice, we performed ELISA assays to check the IFN-γ serum levels. C57BL/6 mice were injected with irradiated MOSEC tumor cells and/or α-GalCer. Five hours after injection, sera were collected from the different groups of mice and assayed for IFN-γ production by ELISA analysis. As shown in

Discussion

In the current study, we characterized the antitumor effects generated by co-administration of irradiated tumor cell-based vaccines with α-GalCer against ovarian cancer using two different mouse models. We observed that treatment with α-GalCer leads to an increase in the IFN-γ serum levels in the presence or absence of irradiated MOSEC tumor cells. Administration of irradiated MOSEC tumor cells with adjuvant α-GalCer generated significant protective and therapeutic antitumor effects against

Acknowledgements

We would like to thank Dr. T.-C. Wu for critical review of the manuscript. This work was supported by ovarian cancer grants from the Alliance for Cancer Gene Therapy (ACGT), the NCDGG (1U19 CA113341-01) and the American Cancer Society (ACS).

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