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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online October 21, 2004 as doi:10.1096/fj.04-2355fje. |
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* Department of Radiation Oncology, Heidelberg Medical School, Heidelberg, Germany;
The Scripps Research Institute, Department of Cell Biology, La Jolla, California, USA;
Charité Children’s Hospital, Department of Pediatric Oncology, Berlin, Germany;
Schering AG, Berlin, Germany; and
|| The Scripps Research Institute, Department of Immunology, La Jolla, California, USA
1Correspondence: The Scripps Research Institute, Department of Immunology, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. Email: reisfeld{at}scripps.edu
SPECIFIC AIMS
The purpose of this study was to demonstrate the effectiveness of the multidrug resistance-mediating protein MDR-1 as a target for T cell-based immunotherapy. We intended to effectively prime CD8+ T cells to recognize and destroy tumor cells overexpressing MDR-1. We constructed an oral DNA vaccine encoding murine MDR-1 and carried by a strain of attenuated Salmonella typhimurium. We tested the effect of our construct against two murine MDR-1-positive tumor entities, lung and colon carcinoma, in a prophylactic and a therapeutic setting.
PRINCIPAL FINDINGS
1. Prophylactive treatment prolongs lifespan
Three time oral vaccination at 2 wk intervals effectively prolonged the survival of mice challenged intravenously with a lethal dose of either syngeneic murine colon carcinoma or Lewis lung carcinoma cells overexpressing MDR-1. Death from lung metastases of the respective tumors was significantly delayed after treatment. No effect was observed after treatment with Salmonella delivering the empty, non-MDR-1 encoding vector (Fig. 1
).
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2. Immunity is antigen-specific and CD8+ T cell mediated
Absence of the antigen on otherwise identical tumor cell lines completely abrogated the effect, as did in vivo depletion of CD8+ T cells. In vitro confrontation of effector cells with MDR-1 expressing cells led to up-regulation of T cell activation markers. These findings also translated into in vitro lysis of tumor target cells. In contrast, we did not observe intubation of tumor growth of MDR-1-negative tumors (Fig. 2
).
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3. The vaccine is effective against established tumors
Our vaccine proved effective when administered as a one time treatment of established lung metastases of a syngeneic murine colon carcinoma. We observed an effect against subcutaneous tumors (Fig. 2A
). No effect could be seen against the MDR-1 negative parental tumor cell line when implanted at the same time, indicating antigen specificity and the absence of a distant bystander effect (Fig. 2B
).
CONCLUSIONS AND SIGNIFICANCE
The up-regulation of multidrug resistance-mediating transporters is often associated with therapy failure. Thus, much effort has focused in the years since its discovery on means to disrupt MDR function including such different molecules as antibodies, antisense oligonucleotides, cyclosporin, verapamil, and others. Here we report for the first time the induction of an effective, T cell-mediated immune response against MDR-1 positive tumor cell lines via an oral vaccine leading to the destruction of the tumor cells. Since chemotherapy often induces overexpression of multidrug resistance-mediating proteins on tumor cells and subsequent therapy failure, our findings may offer an effective way to overcome this challenge. Our findings add to previous observations by other groups that demonstrate the existence of MDR-specific T cells in the circulation of patients suffering from cancer. The antigen MDR-1 functions in this study were selected as an example of a multitude of molecules whose expression pattern can be influenced by existing therapy modalities.
Immunotherapy strongly relies on the presence of sufficient antigen on the target cells. In the case of the chosen antigen MDR-1, overexpression is often found in a variety of tumor entities. Specifically, chemotherapy can lead to up-regulation of an antigen such as MDR-1, which in turn marks the tumor cell for ready destruction by cytotoxic T cells (Fig. 3
).
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Thus, chemotherapy may very well render the tumor cells left post therapy vulnerable to destruction by cytotoxic T cells. On the other hand, tumor cells evading immunotherapy through insufficient expression of MDR-1 may be rendered sensitive to chemotherapy.
FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2355fje;
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) on one flank and CT-26-KSA cells (
) on the opposite flank to investigate any bystander effect against MDR-1 (–) cell lines due to activation of T cell clones against additional antigens. These experiments were performed in a subcutaneous setting. Sides of inoculation were alternated. The animals were immunized once 5 days after tumor cell inoculation. Controls included animals immunized with pcDNA3.1 (P<0.05 at day 25 after challenge) and animals challenged on only one flank with the respective tumor cell line with comparable growth characteristics (data not shown). B) Multidrug resistant, MDR-1 positive (right) and MDR-1 negative subcutaneous CT-26 tumors (left) are depicted 20 days after tumor cell inoculation. The animal was immunized once on day five after tumor cell inoculation.