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

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 naïve 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.

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