Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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