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

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Regulatory T cell (Treg) is one of the major immunosuppressors in tumor-bearing hosts. Although Treg-depletion therapy has been shown to induce a complete cure in tumor-bearing mice, this is not always successful treatment. Using 3-methylcholanthrene (MCA)-induced primary mouse tumors, we examined the distinct regulation of Treg-mediated immunosuppression between carcinomas and sarcomas. We demonstrated that the numbers of Tregs were greatly increased in SCC-bearing mice compared with sarcoma-bearing mice. This appeared to be because SCC produced higher levels of active TGF-β, which is essential for inducing Tregs, compared with sarcoma. Moreover, SCC, but not sarcomas were refractory to Treg-depletion therapy by anti-CD25 mAb administration. 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 of Treg recovery and induced a complete cure in SCC-bearing mice. Thus, we first demonstrated the refractoriness of mouse carcinoma against Treg-depletion therapy using anti-CD25 mAb administration. 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.
2010-04-10