Artificial antigen-presenting cells expressing CD80, CD70, and 4-1BB ligand efficiently expand functional T cells specific to tumor-associated antigens.
Professional antigen-presenting cells (APCs), notably dendritic cells (DCs), are the most potent for expanding antigen-specific T cells ex vivo. However, the labor-intensive and expensive procedure for customized preparation of autologous APCs has hampered their broad clinical application. Artificial APC (aAPC) systems, which can be readily prepared from off-the-shelf components, have been proposed as a promising alternative to custom-made professional APCs. Here, in order to develop a novel aAPC system, we established K562 erythroleukemia cells expressing different combinations of co-stimulatory molecule ligands, CD80, CD70, and/or 4-1BB ligand (4-1BBL). When nucleofected with in vitro-generated mRNA encoding a tumor-associated antigen, MART-1, the K562 cells expressing all of CD80, CD70, and 4-1BBL were the most efficient for expansion of functional T cells specific to an HLA-A2-restricted immunodominant epitope, MART-126-35. In addition, only the K562 cells expressing all three of these co-stimulatory molecule ligands could clearly expand T cells specific to other less immunogenic antigen epitopes, gp100154-162 and Cyp1B1239-247, through transfection with in vitro generated gp100 and Cyp1B1 mRNA, respectively. These results indicated that non-redundant and synergistic effects of co-stimulation via CD28/CD80, CD27/CD70, and 4-1BB/4-1BBL might be critical for eliciting efficient expansion of T cells; co-stimulation via the 4-1BB/4-1BBL interaction might expand antigen-specific T cells by preventing apoptotic cell death triggered by specific antigens in the presence of the CD28/CD80 and CD27/CD70 signaling. Taken together, our findings suggested that this K562-based aAPC system expressing CD80, CD70, and 4-1BBL would be useful for efficiently stimulating functional antigen-specific T cells ex vivo, in particular when detailed information on the epitope specificities is unavailable.
Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Wanyong
W
Zeng
Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Mei
M
Su
Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Karen S
KS
Anderson
Cancer Vaccine Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Department of Immunology and Immunotherapy, Kurume University School of Medicine, Kurume, Japan. Electronic address: tsasada@med.kurume-u.ac.jp.
Tetsuro
T
Sasada
D053330:4-1BB Ligand / Q000276:immunology*; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D053282:CD27 Ligand / Q000276:immunology*; D049109:Cell Proliferation; D065633:Cytochrome P-450 CYP1B1 / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D020014:K562 Cells; D008213:Lymphocyte Activation; D009363:Neoplasm Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D053330:4-1BB Ligand; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D053282:CD27 Ligand; D000939:Epitopes; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1
Antigen-presenting cell; Apoptotic cell death; Co-stimulatory molecule; T cell; Tumor-associated antigen