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lüll Transforming growth factor-beta receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers Wallace A; Kapoor V; Sun J; Mrass P; Weninger W; Heitjan DF; June C; Kaiser LR; Ling LE; Albelda SMClin Cancer Res 2008[Jun]; 14 (12): 3966-74PURPOSE: Adoptive cellular immunotherapy is a promising approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T cells at the effector phase. Transforming growth factor-beta (TGF-beta) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions. We thus hypothesized that systemic blockade of TGF-beta signaling combined with adoptive T-cell transfer would enhance the effectiveness of the therapy. EXPERIMENTAL DESIGN: Flank tumors were generated in mice using the chicken ovalbumin-expressing thymoma cell line, EG7. Splenocytes from transgenic OT-1 mice (whose CD8 T cells recognize an immunodominant peptide in chicken ovalbumin) were activated in vitro and adoptively transferred into mice bearing large tumors in the presence or absence of an orally available TGF-beta receptor-I kinase blocker (SM16). RESULTS: We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed that TGF-beta receptor blockade increased the persistence of adoptively transferred T cells in the spleen and lymph nodes, increased numbers of adoptively transferred T cells within tumors, increased activation of these infiltrating T cells, and altered the tumor microenvironment with a significant increase in tumor necrosis factor-alpha and decrease in arginase mRNA expression. CONCLUSIONS: We found that systemic blockade of TGF-beta receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.|*Immunotherapy, Adoptive[MESH]|Animals[MESH]|Azabicyclo Compounds/*therapeutic use[MESH]|CD8-Positive T-Lymphocytes/metabolism/pathology[MESH]|Combined Modality Therapy[MESH]|Drug Evaluation, Preclinical[MESH]|Female[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Transgenic[MESH]|Neoplasm Transplantation[MESH]|Neoplasms/immunology/pathology/*therapy[MESH]|Receptors, Transforming Growth Factor beta/*antagonists & inhibitors[MESH]|Treatment Outcome[MESH]|Tumor Burden/drug effects/immunology[MESH]|Tumor Cells, Cultured[MESH] |