Transforming Growth Factor-β Receptor Blockade Augments the Effectiveness of Adoptive T-Cell Therapy of Established Solid Cancers

• Published in: Clinical cancer research 2008-06, Vol.14 (12), p.3966-3974
• Main Authors: WALLACE, Africa, KAPOOR, Veena, JING SUN, MRASS, Paul, WENINGER, Wolfgang, HEITJAN, Daniel F, JUNE, Carl, KAISER, Larry R, LING, Leona E, ALBELDA, Steven M
• Format: Article
• Language: English
• Subjects: adoptive transfer; Animals; Antineoplastic agents; Azabicyclo Compounds - therapeutic use; Biological and medical sciences; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Combined Modality Therapy; cytokines; cytotoxic T-cells; Drug Evaluation, Preclinical; Female; immunosuppression; Immunotherapy, Adoptive; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Transplantation; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Pharmacology. Drug treatments; Receptors, Transforming Growth Factor beta - antagonists & inhibitors; TGF-β; Treatment Outcome; Tumor Burden - drug effects; Tumor Burden - immunology; Tumor Cells, Cultured; tumor immunology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-08-0356

Purpose: 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-β (TGF-β) 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-β 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-β 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-β 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-α and decrease in arginase mRNA expression. Conclusions: We found that systemic blockade of TGF-β receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.