3-Methylcholanthrene-induced transforming growth factor-beta-producing carcinomas, but not sarcomas, are refractory to regulatory T cell-depletion therapy.
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)-beta, 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-beta 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-beta mAb to induce a complete cure of tumor-bearing hosts.
Division of Immunoregulation, Section of Disease Control, Institute for Genetic Medicine, and Hokkaido University, Sapporo, Japan.
Kenji
K
Chamoto
Daiko
D
Wakita
Takayuki
T
Ohkuri
Yusuke
Y
Uchinami
Kouji
K
Matsushima
Hidemitsu
H
Kitamura
Takashi
T
Nishimura
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D005260:Female; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008212:Lymphocyte Depletion; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D012509:Sarcoma / Q000139:chemically induced / Q000276:immunology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D019139:Tumor Escape
D000911:Antibodies, Monoclonal; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D008748:Methylcholanthrene