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.