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PLoS One. 2014 Jan 9;9(1):e85398. doi: 10.1371/journal.pone.0085398. eCollection 2014.

Effective chemoimmunotherapy with anti-TGFβ antibody and cyclophosphamide in a mouse model of breast cancer.

Author information

1
Basic Science Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, United States of America ; Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
2
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
3
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
4
Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
5
Genzyme Corporation, Framingham, Massachusetts, United States of America.

Abstract

TGFβ is reportedly responsible for accumulation of CD4(+)Foxp3(+) regulatory T cells (Tregs) in tumor. Thus, we treated mouse 4T1 mammary carcinoma with 1D11, a neutralizing anti-TGFβ (1,2,3) antibody. The treatment delayed tumor growth, but unexpectedly increased the proportion of Tregs in tumor. In vitro, 1D11 enhanced while TGFβ potently inhibited the proliferation of Tregs. To enhance the anti-tumor effects, 1D11 was administered with cyclophosphamide which was reported to eliminate intratumoral Tregs. This combination resulted in long term tumor-free survival of up to 80% of mice, and the tumor-free mice were more resistant to re-challenge with tumor. To examine the phenotype of tumor infiltrating immune cells, 4T1-tumor bearing mice were treated with 1D11 and a lower dose of cyclophosphamide. This treatment markedly inhibited tumor growth, and was accompanied by massive infiltration of IFNγ-producing T cells. Furthermore, this combination markedly decreased the number of splenic CD11b(+)Gr1(+) cells, and increased their expression levels of MHC II and CD80. In a spontaneous 4T1 lung metastasis model with resection of primary tumor, this combination therapy markedly increased the survival of mice, indicating it was effective in reducing lethal metastasis burden. Taken together, our data show that anti-TGFβ antibody and cyclophosphamide represents an effective chemoimmunotherapeutic combination.

PMID:
24416401
PMCID:
PMC3887137
DOI:
10.1371/journal.pone.0085398
[Indexed for MEDLINE]
Free PMC Article

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