- 作者: Chih-Chun Wen, Hui-Ming Chen, Swey-Shen Chen, Li-Ting Huang, Wei-Ting Chang, Wen-Chi Wei, Li-Chen Chou, Palanisamy Arulselvan, Jin-Bin Wu, Sheng-Chu Kuo and Ning-Sun Yang
- 作者服務機構: Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
Background: 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.
Methods: In this study we evaluated the ability of three MDAs (colchicine and two 2-phenl-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.
Results: 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.
Conclusions: 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.
- 中文關鍵字: --
- 英文關鍵字: immunogenic cell death; colchicine; 2-phenyl-4-quinolone; dendritic cells; cancer vaccine