Abstract
Dendritic cells (DC) play a major role during the priming phase of anti-tumor immunization, as they are required for an efficient tumor-associated antigens presentation. At least one dendritic cell-based therapy has already been successfully approved by regulators for clinical application in prostate cancer patients. Moreover, DC development is dependent on the granulocyte macrophage colony stimulating factor (GM-CSF), a cytokine that has been successfully used as a potent inducer of anti-tumoral immunity. To better understand the relation between DC and GM-CSF in anti-tumor immunity, we studied the DC function in mice lacking the cytokine receptor common subunit beta (βc-/-) for GM-CSF, IL-3 and IL-5 and immunized with irradiated tumor cells. Such immunization induces a protective, specific tumor immunization in wild-type mice, while βc-/- mice failed to mount an immune response. Upon in vitro stimulation, DC from βc-/- mice (DCβc-/-) are unable to undergo a full maturation level. In vivo experiments show that they lack the ability to prevent tumor growth, in contrast to DCWT. Moreover, matured DCWT rescued immunization in βc-/- mice. DC maturation is dependent on a functional pathway involving GM-CSF signaling through a biologically functional receptor. These findings may contribute to new strategies for efficient anti-tumor immunotherapies.
Highlights
Advances in understanding the complex mechanisms of immune regulation in cancer biology have provided a solid foundation for developing tumor immunotherapy
To evaluate the role of granulocyte macrophage colony stimulating factor (GM-CSF) signaling in the anti-tumor immunization process, C57BL/6
We can demonstrate that both the release of GM-CSF at the vaccine site and functional GM-CSF receptors are needed for a potent anti-tumor immune response
Summary
Advances in understanding the complex mechanisms of immune regulation in cancer biology have provided a solid foundation for developing tumor immunotherapy. As dendritic cells (DC) are responsible for processing and presenting tumor antigens for the priming of anti-tumor cytotoxic T lymphocytes, research efforts on exploiting their properties for cancer immunotherapy have been developed over the last decades [1,2,3]. In this way, autologous DC loaded with tumor-associated antigen (TAA) [4,5], DC matured ex vivo [6,7], DC genetically modified to express tumor antigen genes (such as PSA and MAGE-1) or DC transformed to express immunomodulatory molecule genes such as IL-12 and granulocyte macrophage colony stimulating factor (GM-CSF) [8] have been used to initiate anti-tumor immunotherapies.
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