3‐Methylcholanthrene‐induced transforming growth factor‐β‐producing carcinomas, but not sarcomas, are refractory to regulatory T cell‐depletion therapy

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Abstract
Regulatory T cells (Tregs) are major immunosuppressors in tumor‐bearing hosts. Although Treg‐depletion therapy has been shown to induce a complete cure in tumor‐bearing mice, this treatment is not always successful. Using 3‐methylcholanthrene‐induced primary mouse tumors, we examined the distinct regulation of Treg‐mediated immunosuppression between carcinomas and sarcomas. We showed that the number of Tregs was greatly increased in squamous cell carcinoma (SCC)‐bearing mice compared with sarcoma‐bearing mice. This appeared to be because SCC produced higher levels of active transforming growth factor (TGF)‐β, which is essential for inducing Tregs, compared with sarcoma. Moreover, SCC, but not sarcomas, were refractory to Treg‐depletion therapy by treatment with anti‐CD25 mAb. The refractoriness of SCC against Treg‐depletion therapy was due to the rapid recovery of Tregs in SCC‐bearing mice compared with sarcoma‐bearing mice. However, combination treatment of anti‐TGF‐β mAb with anti‐CD25 mAb caused a significant reduction in Treg recovery and induced a complete cure in SCC‐bearing mice. Thus, we showed the refractoriness of mouse carcinoma against Treg‐depletion therapy using anti‐CD25 mAb treatment. We also proposed a novel Treg‐blocking combination therapy using anti‐CD25 mAb and anti‐TGF‐β mAb to induce a complete cure of tumor‐bearing hosts.(Cancer Sci 2010; 101: 855–861)

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