Abstract
Background: Dendritic cell (DC) vaccine is a hopeful approach for cancer treatment. In clinical trials, DC vaccines have produced clinical responses in some cancer patients. However, DC vaccines efficacy is not satisfactory in most types of cancer and more efforts must be done to improve their effectiveness in advanced cancers. Understanding the influence of tumor cells and tumor stromal cells on DCs and the antitumor activity of ex vivo generated DCs in the tumor microenvironment can help to augment antitumor efficiency of ex vivo generated DCs. In a fibrosarcoma tumor model, we explored effects of the tumor microenvironment on the antitumor efficacy of ex vivo generated DCs. Methods: DCs were generated from mouse bone marrow precursor cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). DCs were pulsed with tumor antigens and matured in the presence of tumor necrosis factor-alpha (TNF-α), lipopolysaccharide (LPS), or TNF-α plus LPS. Mature or immature DCs were injected subcutaneously before tumor inoculation or were directly injected into the tumor tissue. Results: Tumor antigen-pulsed DCs matured in the presence of TNF-α plus LPS showed appropriate functionality in vitro, including IL-12 secretion and induction of lymphocyte proliferation. Tumor lysate-loaded DCs matured in the presence of TNF-α did not show appropriate antitumor function in vivo. Injection of antigen-unpulsed mature DCs two days before tumor inoculation resulted in antitumor effects. In contrast, injection of immature DCs directly into the tumor tissue enhanced the tumor growth. Conclusion: These results suggest that tumor cells, tumor stromal cells, or tumor derived factors can influence DCs to have tumor-promoting function. Appropriate maturation induction in ex vivo generated DCs and manipulating the tumor microenvironment before DC vaccination may improve antitumor activity of DC vaccines in cancer patients.
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