This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wallace, A. Articles by Albelda, S. M. Search for Related Content PubMed PubMed Citation Articles by Wallace, A. Articles by Albelda, S. M.

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

Authors' Affiliations: ¹ Thoracic Oncology Research Laboratory and ² Department of Biostatistics and Epidemiology, University of Pennsylvania; ³ Wistar Institute, Philadelphia, Pennsylvania, and ⁴ Oncology Cell Signaling, Biogen Idec, Cambridge Center, Cambridge, Massachusetts

Requests for reprints: Steven Albelda, 1016B ARC, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA 19104-4318. Phone: 215-573-9969; Fax: 215-573-4469; E-mail: albelda{at}mail.med.upenn.edu.

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- 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.

This article has been cited by other articles:

				S. Kim, G. Buchlis, Z. G. Fridlender, J. Sun, V. Kapoor, G. Cheng, A. Haas, H. K. Cheung, X. Zhang, M. Corbley, et al. Systemic Blockade of Transforming Growth Factor-{beta} Signaling Augments the Efficacy of Immunogene Therapy Cancer Res., December 15, 2008; 68(24): 10247 - 10256. [Abstract] [Full Text] [PDF]