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Cellular immunotherapy may provide a strategy to overcome the poor prognosis of metastatic and recurrent rhabdomyosarcoma (RMS) under the current regimen of polychemotherapy. Because little is known about resistance mechanisms of RMS to cytotoxic T cells, we investigated RMS cell lines and biopsy specimens for expression and function of immune costimulatory receptors and anti-apoptotic molecules by RT-PCR, Western blot analysis, IHC, and cytotoxicity assays using siRNA or transfection-modified RMS cell lines, together with engineered RMS-directed cytotoxic T cells specific for the fetal acetylcholine receptor. We found that costimulatory CD80 and CD86 were consistently absent from all RMSs tested, whereas inducible T-cell co-stimulator ligand (ICOS-L; alias B7H2) was expressed by a subset of RMSs and was inducible by tumor necrosis factor α in two of five RMS cell lines. Anti-apoptotic survivin, along with other inhibitor of apoptosis (IAP) family members (cIAP1, cIAP2, and X-linked inhibitor of apoptosis protein), was overexpressed by RMS cell lines and biopsy specimens. Down-regulation of survivin by siRNA or pharmacologically in RMS cells increased their susceptibility toward a T-cell attack, whereas induction of ICOS-L did not. Treatment of RMS-bearing Rag(-/-) mice with fetal acetylcholine receptor-specific chimeric T cells delayed xenograft growth; however, this happened without definitive tumor eradication. Combined blockade of survivin and application of chimeric T cells in vivo suppressed tumor proliferation during survivin inhibition. In conclusion, survivin blockade provides a strategy to sensitize RMS cells for T-cell-based therapy.

Original publication

DOI

10.1016/j.ajpath.2013.02.017

Type

Journal article

Journal

Am J Pathol

Publication Date

06/2013

Volume

182

Pages

2121 - 2131

Keywords

Animals, B7-1 Antigen, B7-2 Antigen, Biopsy, CD28 Antigens, Child, Preschool, Costimulatory and Inhibitory T-Cell Receptors, Cytotoxicity, Immunologic, Female, Gene Knockdown Techniques, Humans, Immunotherapy, Adoptive, Inducible T-Cell Co-Stimulator Ligand, Infant, Inhibitor of Apoptosis Proteins, Ligands, Male, Mice, Mice, Knockout, Neoplasm Transplantation, Receptors, Cholinergic, Rhabdomyosarcoma, Signal Transduction, T-Lymphocytes, T-Lymphocytes, Cytotoxic, Transplantation, Heterologous, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha