Survivin blockade sensitizes rhabdomyosarcoma cells for lysis by fetal acetylcholine receptor-redirected T cells.

Journal article

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.

Authors: Simon-Keller, K; Paschen, A; Hombach, A; Ströbel, P; Coindre, J

• Publication status: Published
• Journal: American journal of pathology
• Volume: 182
• Issue: 6
• Pages: 2121-2131
• Publication date: 2013-06-01
• DOI: 10.1016/j.ajpath.2013.02.017
• EISSN: 1525-2191
• ISSN: 0002-9440
• Language: English
• Keywords: Ligands; Animals; Tumor Necrosis Factor-alpha; Receptors, Cholinergic; Gene Knockdown Techniques; Infant; Immunotherapy, Adoptive; Cytotoxicity, Immunologic; Inducible T-Cell Co-Stimulator Ligand; Inhibitor of Apoptosis Proteins; Male; T-Lymphocytes; Mice; Costimulatory and Inhibitory T-Cell Receptors; Antigens, CD80; Child, Preschool; Mice, Knockout; Antigens, CD28; Biopsy; Antigens, CD86; T-Lymphocytes, Cytotoxic; Female; Signal Transduction; Humans; Tumor Cells, Cultured; Neoplasm Transplantation; Rhabdomyosarcoma; Transplantation, Heterologous