adoptive transfer of sirna cblb-silenced cd8+ t lymphocytes augments tumor vaccine efficacy in a b16 melanoma model过继转移的sirna cblb-silenced cd8 + t淋巴细胞增加肿瘤疫苗功效在黑色素瘤b16转椅模型.pdfVIP

Adoptive Transfer of siRNA Cblb-Silenced CD8+ T Lymphocytes Augments Tumor Vaccine Efficacy in a B16 Melanoma Model Reinhard Hinterleitner1., Thomas Gruber1., Christa Pfeifhofer-Obermair1., Christina Lutz- 1,2. 3 4 5 4 Nicoladoni , Alexander Tzankov , Manfred Schuster , Josef M. Penninger , Hans Loibner , ¨ 4 2,6. 1 . Gunther Lametschwandtner , Dominik Wolf , Gottfried Baier * 1 Department of Pharmacology and Genetics, Medical University Innsbruck, Innsbruck, Austria, 2 Laboratory of Tumor Immunology, Tyrolean Cancer Research Institute, Innsbruck, Austria, 3 Institute of Pathology, University Hospital Basel, Basel, Switzerland, 4 Apeiron-Biologics AG, Vienna, Austria, 5 Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria, 6 Department of Hematology and Oncology, Medical University Bonn, Bonn, Germany Abstract The ubiquitin ligase Cbl-b is an established regulator of T cell immune response thresholds. We recently showed that adoptive cell transfer (ACT) of cblb2/ 2 CD8+ T cells enhances dendritic cell (DC) immunization-mediated anti-tumor effects in immune-competent recipients. However, translation of cblb targeting to clinically applicable concepts requires that inhibition of cblb activity be transient and reversible. Here we provide experimental evidence that inhibition of cblb using chemically synthesized siRNA has such potential. Silencing cblb expression by ex vivo siRNA transfection of polyclonal CD8+ T cells prior to ACT increased T cell tumor infiltration, significantly delayed tumor outgrowth, and increased survival rates of tumor-bearing mice. As shown