Abstract
BackgroundThe eradication of large, established tumors by active immunotherapy is a major challenge because of the numerous cancer evasion mechanisms that exist. This study aimed to establish a novel combination therapy consisting of messenger RNA (mRNA)-based cancer vaccines and radiation, which would facilitate the effective treatment of established tumors with aggressive growth kinetics.MethodsThe combination of a tumor-specific mRNA-based vaccination with radiation was tested in two syngeneic tumor models, a highly immunogenic E.G7-OVA and a low immunogenic Lewis lung cancer (LLC). The molecular mechanism induced by the combination therapy was evaluated via gene expression arrays as well as flow cytometry analyses of tumor infiltrating cells.ResultsIn both tumor models we demonstrated that a combination of mRNA-based immunotherapy with radiation results in a strong synergistic anti-tumor effect. This was manifested as either complete tumor eradication or delay in tumor growth. Gene expression analysis of mouse tumors revealed a variety of substantial changes at the tumor site following radiation. Genes associated with antigen presentation, infiltration of immune cells, adhesion, and activation of the innate immune system were upregulated. A combination of radiation and immunotherapy induced significant downregulation of tumor associated factors and upregulation of tumor suppressors. Moreover, combination therapy significantly increased CD4+, CD8+ and NKT cell infiltration of mouse tumors.ConclusionOur data provide a scientific rationale for combining immunotherapy with radiation and provide a basis for the development of more potent anti-cancer therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/1748-717X-9-180) contains supplementary material, which is available to authorized users.
Highlights
Despite recent advances in the field of cancer immunotherapy, the treatment of large, advanced tumors remains very challenging and the clinical outcome is often disappointing [1,2]
The delayed response consists of increased protein synthesis, induction of Fas signaling, upregulation of costimulatory molecules and induction of adhesion molecules [4]. These changes at the radiated tumor site can significantly affect the action of immune cells which are already present or which will be recruited to the tumor site following immunotherapy
We have previously shown that messenger RNA (mRNA)-based twocomponent cancer vaccines consisting of free and complexed mRNA induce sustained, balanced immune responses and mediate strong tumor protection in vivo, represent a novel promising approach to cancer therapy [5]
Summary
Despite recent advances in the field of cancer immunotherapy, the treatment of large, advanced tumors remains very challenging and the clinical outcome is often disappointing [1,2]. Because of our experience in mRNAbased cancer vaccine development we sought to determine if mRNA immunotherapy and local tumor radiation could act synergistically to inhibit the growth of large, Different strategies for combined anti-tumor therapy have already been tested. Among these approaches, which include chemotherapy, small molecule inhibitors and monoclonal antibodies, radiation therapy is the most interesting candidate for combining with active immunotherapy. The delayed response consists of increased protein synthesis, induction of Fas signaling, upregulation of costimulatory molecules and induction of adhesion molecules [4] These changes at the radiated tumor site can significantly affect the action of immune cells which are already present or which will be recruited to the tumor site following immunotherapy. This study aimed to establish a novel combination therapy consisting of messenger RNA (mRNA)-based cancer vaccines and radiation, which would facilitate the effective treatment of established tumors with aggressive growth kinetics
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