Molecular and Functional Conditioning of Dendritic Cells for DC-based Immunotherapy against Tumours - Guiding the “Misguided”

Abstract

The concept of DC-based tumour vaccine has been tested both experimentally and clinically during the last one and half decades. It aims to induce and establish specific immunity against tumour cells, or the so-called “mutated self” antigens which are understandably mostly weak immunogens to the host. Such a live cell-based approach is also known to be extremely sensitive to, hence its efficacy inevitably limited by, the tumour microenvironment. Certain immunosuppressive mechanisms triggered by tumour cells or the derivatives are believed to be a major obstacle. Under the tumourigenic environment, DC can even be switched to induce tolerance instead. Its clinical application has thus been hindered by limited success and a lack of general efficacy both in animal studies and clinical trials. In order to develop the DC-based tumour vaccine with high efficacy and stability, we have designed, tested and compared different ways of enhancing DC immunogenicity by functional conditioning of the cell vectors, targeting both the positive and negative regulators of DC functions. Findings from our studies have shown that the expression of several important DC functional molecules (CD80, CD86, CD40, IL-12) could be selectively enhanced by over expressing the specific genes. Upon interactions with the tumour cells, however, these DC rapidly lost again their immunogenic properties, featuring a down-regulated IL-12 but highly up-regulated IL-10 expression. When these molecularly modified DC were used as the vectors to deliver tumour antigens, there was little or no enhancement in their in vivo anti-tumour effect observed. In contrast, we demonstrated further that when the vaccines were delivered by DCs devoid or knock-down of the IL-10 gene, strong anti-tumour immunity could be readily induced. These DCs lacking IL-10 were highly immunogenic, expressing enhanced levels of surface MHC class II molecules and Th1-related cytokines. By inducing tumour-specific killing and through the establishment of immunological memory, the vaccines delivered by IL-10-/-DCs could evoke strong therapeutic and protective immunity in vivo. It points to a crucial role of DC-derived IL-10 in inhibiting successful DC-based immunotherapy against tumours. In conclusion, our experimental evidence indicates that the most effective way to enhance the efficacy of DC-based tumour immunotherapy is to alleviate the negative arm of immune regulation (釜底抽薪). This approach has now been tested by us successfully in 7 experimental animal models of 2 very different types of tumours (melanoma, hepatoma). The findings are therefore expected to have great clinical impact once being translated into the treatment of malignant, and potentially infectious, diseases in man.