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Specific microtubule-depolymerizing agents augment efficacy of dendritic cell-based cancer vaccines
- Equal contributors
1 Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan
2 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
3 Department and Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
4 Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, CA, USA
5 Department of Molecular Biology, The Scripps Research Institute, San Diego, CA, USA
6 Department of Food and Nutrition, Providence University, Taichung, Taiwan
7 Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan
Journal of Biomedical Science 2011, 18:44 doi:10.1186/1423-0127-18-44Published: 20 June 2011
Damage-associated molecular patterns (DAMPs) are associated with immunogenic cell death and have the ability to enhance maturation and antigen presentation of dendritic cells (DCs). Specific microtubule-depolymerizing agents (MDAs) such as colchicine have been shown to confer anti-cancer activity and also trigger activation of DCs.
In this study, we evaluated the ability of three MDAs (colchicine and two 2-phenyl-4-quinolone analogues) to induce immunogenic cell death in test tumor cells, activate DCs, and augment T-cell proliferation activity. These MDAs were further evaluated for use as an adjuvant in a tumor cell lysate-pulsed DC vaccine.
The three test phytochemicals considerably increased the expression of DAMPs including HSP70, HSP90 and HMGB1, but had no effect on expression of calreticulin (CRT). DC vaccines pulsed with MDA-treated tumor cell lysates had a significant effect on tumor growth, showed cytotoxic T-lymphocyte activity against tumors, and increased the survival rate of test mice. In vivo antibody depletion experiments suggested that CD8+ and NK cells, but not CD4+ cells, were the main effector cells responsible for the observed anti-tumor activity. In addition, culture of DCs with GM-CSF and IL-4 during the pulsing and stimulation period significantly increased the production of IL-12 and decreased production of IL-10. MDAs also induced phenotypic maturation of DCs and augmented CD4+ and CD8+ T-cell proliferation when co-cultured with DCs.
Specific MDAs including the clinical drug, colchicine, can induce immunogenic cell death in tumor cells, and DCs pulsed with MDA-treated tumor cell lysates (TCLs) can generate potent anti-tumor immunity in mice. This approach may warrant future clinical evaluation as a cancer vaccine.