title: siRNA-mediated silencing of PD-1 ligands enhances tumor-specific human T-cell effector functions.
abstract: Adoptive cell therapy using tumor-specific T cells is a promising strategy for treating patients with malignancy. However, accumulating evidences have demonstrated that optimal function of tumor-reactive T cells is often attenuated by negative regulatory signal(s) delivered through receptors, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), and their cognate ligands. Although systemic blocking of these molecules needs careful attention on the risk of uncontrolled immune activation, selective inhibition of negative signals in tumor-specific T cells by their genetic modification is an attractive approach to overcome immunological suppression in cancer patients. Here, we demonstrate the improved effector functions of tumor-specific CD4(+) and CD8(+) human T cells by small interfering RNA (siRNA) -mediated silencing of PD-1 ligands, PD-L1 or PD-L2. Tumor antigen MAGE-A4-specific human T-cell clones upregulated the expression of PD-1 ligands upon activation. siRNA-mediated knockdown of PD-L1 or -L2 enhanced the interferon-γ production and antigen-specific cytotoxicity of these cells. Peripheral blood mononuclear cells transduced with a retroviral vector encoding MAGE-A4-specific T-cell receptor α/β chains also increased their effector functions by this modification. These results suggest that siRNA-mediated knockdown of PD-1 ligands is an attractive strategy to inhibit a negative regulatory mechanism of tumor-specific T cells resulting in enhanced efficacy of adoptive T-cell therapy of cancer using genetically modified autologous lymphocytes.
authors: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
authors: K
authors: K
authors: Iwamura
authors: T
authors: T
authors: Kato
authors: Y
authors: Y
authors: Miyahara
authors: H
authors: H
authors: Naota
authors: J
authors: J
authors: Mineno
authors: H
authors: H
authors: Ikeda
authors: H
authors: H
authors: Shiku
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005822:Genetic Vectors; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins; D061027:Programmed Cell Death 1 Ligand 2 Protein; D034741:RNA, Small Interfering; D007371:Interferon-gamma