An Artificial Antigen-Presenting Cell Delivering 11 Immune Molecules Expands Tumor Antigen-Specific CTLs in Ex Vivo and In Vivo Murine Melanoma Models

被引:14
|
作者
Zhang, Lei [1 ]
Song, Shilong [1 ]
Jin, Xiaoxiao [1 ]
Wan, Xin [1 ]
Shahzad, Khawar Ali [1 ]
Pei, Weiya [1 ]
Zhao, Chen [1 ]
Shen, Chuanlai [1 ]
机构
[1] Southeast Univ, Med Sch, Dept Microbiol & Immunol, Nanjing, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
T-CELLS; IMMUNOTHERAPY; EXPANSION; EFFICACY; PEPTIDE; POLYMER; BIOLOGY; IL-2;
D O I
10.1158/2326-6066.CIR-18-0881
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Antigen-presenting cells expand antigen-specific T cells ex vivo and in vivo for tumor immunotherapy, but are time-consuming to generate and, as live cells, raise biosafety concerns. An alternative is found in cell-free artificial antigen-presenting cells (aAPC), but these only present two or three kinds of immune molecules. Here, we describe a multipotent artificial antigen-presenting cell (MaAPC) that delivered 11 kinds of immune moleclues. This MaAPC simulated natural APCs through the concurent coupling of target antigens (H-2K(b)/TRP2(180-188)-Ig dimers and H-2D(b)/gp100(25-33)-Ig dimers), costimulatory molecules (anti-CD28, anti-4-1BB, and anti-CD2), and "self-marker" CD47-Fc onto surface-modified polylactic-co-glycolic acid microparticles (PLGA-MP). These PLGA-MPs also encapsulated cytokines (IL2 and IL15), a chemokine (CCL21), and checkpoint inhibitors (anti-CTLA-4 and anti-PD-1). Culture of MaAPCs with naive T cells for 1 week elevated the frequencies of TRP2(180-188)-specific and gp100(25-33)-specific CTLs to 51.0% and 43.3%, respectively, with enhanced cytotoxicity. Three infusions of MaAPCs inhibited subcutaneous melanoma growth in a mouse model and expanded TRP2(180-188) and gp100(25-33)-specific CTLs 59-86-fold in peripheral blood, 76-77-fold in spleen, and 205-212-fold in tumor tissue, in an antigen-specific manner. Compared with conventional aAPCs carrying two or three immune molecules, the 11-signal MaAPCs exerted greater impact on T cells, including activation, proliferation, cytotoxicity, differentiation to memory CTLs or regulatory T cells and cytokines profiles, without detected side effects. Such MaAPCs could be used to individualize tumor immunotherapy.
引用
收藏
页码:1188 / 1201
页数:14
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