Email updates

Keep up to date with the latest news and content from BMC Immunology and BioMed Central.

Open Access Research article

The timing of TGF-β inhibition affects the generation of antigen-specific CD8+ T Cells

Jon G Quatromoni12*, Eiji Suzuki34, Olugbenga Okusanya12, Brendan F Judy12, Pratik Bhojnagarwala12, Ollin Venegas12, Evgeniy Eruslanov12, Jarrod D Predina12, Steven M Albelda34 and Sunil Singhal12

Author Affiliations

1 Division of Thoracic Surgery, Perelman School of Medicine at the University of Pennsylvania, 6 White Building, 3400 Spruce Street, Philadelphia, PA 19104, USA

2 Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA

3 Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 1015F ARC, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA

4 Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA

For all author emails, please log on.

BMC Immunology 2013, 14:30  doi:10.1186/1471-2172-14-30

Published: 17 July 2013

Abstract

Background

Transforming growth factor (TGF)-β is a potent immunosuppressive cytokine necessary for cancer growth. Animal and human studies have shown that pharmacologic inhibition of TGF-β slows the growth rate of established tumors and occasionally eradicates them altogether. We observed, paradoxically, that inhibiting TGF-β before exposing animals to tumor cells increases tumor growth kinetics. We hypothesized that TGF-β is necessary for the anti-tumor effects of cytotoxic CD8+ T lymphocytes (CTLs) during the early stages of tumor initiation.

Methods

BALB/c mice were pretreated with a blocking soluble TGF-β receptor (sTGF-βR, TGF-β-blockade group, n=20) or IgG2a (Control group, n=20) before tumor inoculation. Tumor size was followed for 6 weeks. In vivo lymphocyte assays and depletion experiments were then performed to investigate the immunological basis of our results. Lastly, animals were pretreated with either sTGF-βR (n=6) or IgG2a (n=6) prior to immunization with an adenoviral vector encoding the human papillomavirus E7 gene (Ad.E7). One week later, flow cytometry was utilized to measure the number of splenic E7-specific CD8+ T cells.

Results

Inhibition of TGF-β before the injection of tumor cells resulted in significantly larger average tumor volumes on days 11, 17, 22, 26 and 32 post tumor-inoculation (p < 0.05). This effect was due to the inhibition of CTLs, as it was not present in mice with severe combined immunodeficiency (SCID) or those depleted of CD8+ T cells. Furthermore, pretreatment with sTGF-βR inhibited tumor-specific CTL activity in a Winn Assay. Tumors grew to a much larger size when mixed with CD8+ T cells from mice pretreated with sTGF-βR than when mixed with CD8+ T cells from mice in the control group: 96 mm3 vs. 22.5 mm3, respectively (p < 0.05). In addition, fewer CD8+ T cells were generated in Ad.E7-immunized mice pretreated with sTGF-βR than in mice from the control group: 0.6% total CD8+ T cells vs. 1.9%, respectively (p < 0.05).

Conclusions

These studies provide the first in vivo evidence that TGF-β may be necessary for anti-tumor immune responses in certain cancers. This finding has important implications for our understanding of anti-tumor immune responses, the role of TGF-β in the immune system, and the future development of TGF-β inhibiting drugs.

Keywords:
Malignant mesothelioma; Tumor immunology; Immune suppression; TGF-β; CD8+ Cytotoxic T cell