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

BMC Immunology

Sunil Singhal²  Steven M Albelda¹  Jarrod D Predina²  Evgeniy Eruslanov²  Ollin Venegas²  Pratik Bhojnagarwala²  Brendan F Judy²  Olugbenga Okusanya²  Eiji Suzuki¹  Jon G Quatromoni² 

[1] Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA;Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA

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

Others  :  1077778
DOI  :  10.1186/1471-2172-14-30

 received in 2013-04-23, accepted in 2013-07-02,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Quatromoni et al.; licensee BioMed Central Ltd.

【 图 表 】

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