Specific microtubule-depolymerizing agents augment efficacy of dendritic cell-based cancer vaccines

Wen Chih-Chun, Chen Hui-Ming, Chen Swey-Shen, Huang Li-Ting, Chang Wei-Ting, Wei Wen-Chi, Chou Li-Chen, Arulselvan Palanisamy, Wu Jin-Bin, Kuo Sheng-Chu, Yang Ning-Sun

Description

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-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. 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.

Sujets

• Colchicine
• Dendritic cell
• Cancer vaccine

Informations

• Publié par: biomed
• Publié le: 01 janvier 2011
• Nombre de lectures: 9
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Wenet al.Journal of Biomedical Science2011,18:44 http://www.jbiomedsci.com/content/18/1/44

R E S E A R C HOpen Access Specific microtubuledepolymerizing agents augment efficacy of dendritic cellbased cancer vaccines 1,2†2,3†2,4,5 22,6 2,7 ChihChun Wen, HuiMing Chen, SweyShen Chen, LiTing Huang , WeiTing Chang, WenChi Wei, 1 21 1*2* LiChen Chou , Palanisamy Arulselvan , JinBin Wu , ShengChu Kuoand NingSun Yang

Abstract 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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. 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 CD4cells, 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 CD4and CD8T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. Keywords:immunogenic cell death, colchicine, 2phenyl4quinolone, dendritic cells, cancer vaccine

Background Cancer vaccines seek to treat malignancies by approaches that induce presentation of tumorassociated + antigens (TAAs) in contexts that elicit potent CD4and + CD8 Tcellresponses and break the tolerance of the host immune system to tumor growth [1,2]. Immunity, including innate immunity and antigenspecific adaptive immunity, and tolerance toward tumors is orchestrated

* Correspondence: [e-mail]; [e-mail] †Contributed equally 1 Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung, Taiwan 2 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan Full list of author information is available at the end of the article

by a network of antigenpresenting cells, the most crucial of which are dendritic cells (DCs) [3,4]. Although clinical trials based on DCbased vaccines have been initiated for certain malignancies [5], unlike in pathogen infection, activation of DCs in tumor microenviron ments is weak and ineffective [1,6]; therefore, the devel opment of DCbased vaccines that can not only induce powerful activation of DCs, but also enhance tumor specific immunity by breaking tolerance is a challenge. Most anticancer chemotherapeutics influence both tumor cells and the associated immune systems [7]. However, the mechanisms that underlie the various cellular activities that induce immune response, and

© 2011 Wen et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.