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

Research output: Contribution to journalArticle

54 Citations (Scopus)

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

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Growth Factor Receptors
Transforming Growth Factors
Cell- and Tissue-Based Therapy
T-Lymphocytes
Neoplasms
Adoptive Transfer
Ovalbumin
Chickens
Adoptive Immunotherapy
Arginase
Tumor Microenvironment
Thymoma
Immunosuppressive Agents
Immunotherapy
Research Design
Phosphotransferases
Spleen
Tumor Necrosis Factor-alpha
Lymph Nodes
Macrophages

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. / Wallace, Africa; Kapoor, Veena; Sun, Jing; Mrass, Paul; Weninger, Wolfgang; Heitjan, Daniel F.; June, Carl; Kaiser, Larry R.; Ling, Leona E.; Albelda, Steven M.

In: Clinical Cancer Research, Vol. 14, No. 12, 15.06.2008, p. 3966-3974.

Research output: Contribution to journalArticle

Wallace, A, Kapoor, V, Sun, J, Mrass, P, Weninger, W, Heitjan, DF, June, C, Kaiser, LR, Ling, LE & Albelda, SM 2008, 'Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers', Clinical Cancer Research, vol. 14, no. 12, pp. 3966-3974. https://doi.org/10.1158/1078-0432.CCR-08-0356
Wallace, Africa ; Kapoor, Veena ; Sun, Jing ; Mrass, Paul ; Weninger, Wolfgang ; Heitjan, Daniel F. ; June, Carl ; Kaiser, Larry R. ; Ling, Leona E. ; Albelda, Steven M. / Transforming growth factor-β receptor blockade augments the effectiveness of adoptive T-cell therapy of established solid cancers. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 12. pp. 3966-3974.
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AU - Heitjan, Daniel F.

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