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

ABSTRACT: 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.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).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.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.

SUBMITTER: Wallace A

PROVIDER: S-EPMC2491721 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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

Wallace Africa A Kapoor Veena V Sun Jing J Mrass Paul P Weninger Wolfgang W Heitjan Daniel F DF June Carl C Kaiser Larry R LR Ling Leona E LE Albelda Steven M SM

Clinical cancer research : an official journal of the American Association for Cancer Research 20080601 12

<h4>Purpose</h4>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-bet ...[more]

PMID: 18559619

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Project description:Dysfunctional pulmonary homeostasis and repair, including diseases such as pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD), and tumorigenesis have been increasing over the past decade, a fact that heavily implicates environmental influences. Several investigations have suggested that in response to increased transforming growth factor--beta (TGF?) signaling, the alveolar type II (ATII) epithelial cell undergoes phenotypic changes that may contribute to the complex pathobiology of PF. We have previously demonstrated that increased tissue stiffness associated with PF is a potent extracellular matrix (ECM) signal for epithelial cell activation of TGF?. The work reported here explores the relationship between tissue stiffness and exposure to environmental stimuli in the activation of TGF?. We hypothesized that exposure of ATII cells to fine particulate matter (PM2.5) will result in enhanced cell contractility, TGF? activation, and subsequent changes to ATII cell phenotype. ATII cells were cultured on increasingly stiff substrates with or without addition of PM2.5. Exposure to PM2.5 resulted in increased activation of TGF?, increased cell contractility, and elongation of ATII cells. Most notably, on 8 kPa substrates, a stiffness greater than normal but less than established fibrotic lung, addition of PM2.5 resulted in increased cortical cell stiffness, enhanced actin staining and cell elongation; a result not seen in the absence of PM2.5. Our work suggests that PM2.5 exposure additionally enhances the existing interaction between ECM stiffness and TGF? that has been previously reported. Furthermore, we show that this additional enhancement is likely a consequence of intracellular reactive oxygen species (ROS) leading to increased TGF? signaling events. These results highlight the importance of both the micromechanical and biochemical environment in lung disease initiation and suggest that individuals in early stages of lung remodeling during fibrosis may be more susceptible than healthy individuals when exposed to environmental injury adjuvants.

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

Publications

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

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