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

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

doi:10.1186/1423-0127-18-44

Abstract

BackgroundDamage-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.MethodsIn 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.ResultsThe 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.ConclusionsSpecific 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.

Highlights

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)
To evaluate whether CMQ and FMQ and colchicine as microtubule-depolymerizing agents, can cause cell death leading to immunogenic cell death, we examined their effect along with the effect of doxorubicin as positive control on cell proliferation of B16 melanoma cells
Depletion of CD8+ T cells and NK cells virtually completely blocked the protective activity of DC vaccines pulsed with CMQ-treated tumor cell lysates (TCLs). These results indicate that tumor-specific CD8+ T cells and NK cells play a crucial role in the observed therapeutic immunity induced by DC vaccines pulsed with CMQ-treated TCLs against B16 melanoma, whereas CD4+ T cells are only partially involved in the antitumor activity

Summary

Introduction

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 microtubuledepolymerizing agents (MDAs) such as colchicine have been shown to confer anti-cancer activity and trigger activation of DCs. Cancer vaccines seek to treat malignancies by approaches that induce presentation of tumor-associated antigens (TAAs) in contexts that elicit potent CD4+ and CD8+ T-cell responses and break the tolerance of the host immune system to tumor growth [1,2]. CRT, HSPs and HMGB1 can function as immunological adjuvants for phagocytosis, cross presentation of tumorderived antigens and antigen processing and presentation by DCs [10]. It is, of interest to investigate the molecular and cellular behaviors of these immunogenic cell death-associated proteins in tumor cell lysates (TCLs) with an eye toward improving the efficacy of TCL-pulsed DC-based vaccines

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