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Abstract 633: Inhibition of TGFβ as a strategy to convert the irradiated tumor into in situ individualized vaccine
- Source :
- Cancer Research. 74:633-633
- Publication Year :
- 2014
- Publisher :
- American Association for Cancer Research (AACR), 2014.
-
Abstract
- Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in two pre-clinical models of metastatic breast cancer and analyzed in patients with metastatic breast cancer treated with local radiotherapy and the TGFβ-neutralizing antibody Fresolimumab. Mice bearing established 4T1 and TSA mouse mammary carcinomas treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Likewise, HLA-A2.1+ metastatic breast cancer patients (n=8) enrolled in NCT01401062 trial of local RT and fresolimumab were examined for CD8+ T cells specific for the tumor antigen survivin by tetramer staining. Three patients developed increased frequencies of survivin-specific CD8+ T cells in the blood during treatment, while two patients negative at baseline became positive. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. Supported by DOD BCRP Multi-Team Award BC100481. Citation Format: Claire I. Vanpouille-Box, Julie M. Diamond, Jiri Zavadil, James Babb, Dörthe Schaue, Mary Helen Barcellos-Hoff, William H. McBride, Silvia C. Formenti, Sandra Demaria. Inhibition of TGFβ as a strategy to convert the irradiated tumor into in situ individualized vaccine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 633. doi:10.1158/1538-7445.AM2014-633
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi...........e4ca946c90ed0e489abf0c37162710f1
- Full Text :
- https://doi.org/10.1158/1538-7445.am2014-633