Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers

Africa Wallace, Veena Kapoor, Jing Sun, Paul Mrass, Wolfgang Weninger, Daniel F. Heitjan, Carl June, Larry R. Kaiser, Leona E. Ling, Steven M. Albelda

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56 Scopus citations

Abstract

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, EG 7. 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 availableTGF-β receptor-l kinase blocker (SM16). Results: We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed thatTGF-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.

Original languageEnglish (US)
Pages (from-to)3966-3974
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number12
DOIs
StatePublished - Jun 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wallace, A., Kapoor, V., Sun, J., Mrass, P., Weninger, W., Heitjan, D. F., June, C., Kaiser, L. R., Ling, L. E., & Albelda, S. M. (2008). Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. Clinical Cancer Research, 14(12), 3966-3974. https://doi.org/10.1158/1078-0432.CCR-08-0356