The achilles heel of cancer therapies is poor specificity. resulting in high cancer recurrence rates and poor survival outcomes. The development of curative treatments is thus focused on strategies that specifically target malignant cells while leaving normal tissues intact. As such, tremendous promise has been invested in using dendritic cells (DC), the most powerful T cell activators known, to induce potent anti-tumor T cell responses. However, DC vaccine strategies have been successful only in the cancer prevention models (immunization, then tumor challenge), while cancer treatment strategies (tumor challenge, then immunization) largely fail. Why? Established mestastic cancers are thought to overwhelm the unprimed immune system by inhibiting the process of dendritic cell (DC) maturation. Normally, DC maturation is essential to na?ve T cell activation in vivo and its inhibition to the tumor-bearing host results in dysfunctional T cell priming. However, in the microenvironment of cell injury and inflammation, the molecular products of injured cells provide potent signals for immature DC to mature. Furthermore, the most powerful cell-injuring agents used in cancer treatment are chemotherapy drugs and radiation. Combining these two concepts, cancer cells injured with chemotherapy/radiation release pro-maturational molecules that may induce immature/inhibited DC to resume growth and differentiation, thereby restoring the patient's endogenous ability to mount anti-tumor T cell responses. This proposal therefore aims to understand how development and function of DC are lost in the cancer patent and how they may be restored by using injured cancer cells as activators. The experimental approach involves using the U937 human leukemic tumor cell as a model and transfectants thereof. The effects of viable and 'injured' U937 tumor cells on DC phenotype will be measured by flow cytometric analysis. Their effects on DC function will be examined via assays in T cell proliferation, in vitro T cell priming. T cell cytokine synthesis, and DC/T cell clustering studies using confocal microscopy. Once these model studies are complete, the phenotypic and functional effects of tumor cells on mature/immature DC from pediatric leukemia patients will be examined, thus allowing precise design of treatment regimes combining radiation and chemotherapy with DC immunotherapy.
|Rad, Ariel N; Pollara, Gabriele; Sohaib, S M Afzal et al. (2003) The differential influence of allogeneic tumor cell death via DNA damage on dendritic cell maturation and antigen presentation. Cancer Res 63:5143-50|