Tumor-derived TGF-beta Mediates Conversion of CD4(+)Foxp3(+) Regulatory T Cells in a Murine Model of Pancreas Cancer

CD4(+)25 Foxp3(+) regulatory T cells (T-reg) play a critical role in the induction of tolerance to tumor-associated antigens and suppression of antitumor immunity. How T-reg are induced in cancer is poorly understood. We reported previously that T-reg are significantly elevated in the peripheral blood of patients with pancreas cancer and that in a murine pancreas cancer model induction of T-reg seems to be transforming growth factor (TGF)-beta dependent. Here we provide additional evidence that T-reg are increased locally within the tumor microenvironment by a mechanism that seems dependent on TGF-beta receptor expression and the presence of tumor derived TGF-beta. The murine pancreas cancer cell line Pan02 produces high levels of TGF-beta both in vitro and in vivo. In contrast, the esophageal murine cancer cell line, Eso2, does not. immunohistochemical staining of Foxp3 in explanted tumors shows an identifiable Population of T-reg in the Pan02 (TGF-beta positive) tumors but not Eso2 (TGF-beta negative). Naive CD4(+)25(-) Foxp3(-) T cells, when adoptively transferred into Rag(-/-) mice, are converted into Foxp3(+) T-reg in the presence of Pan02 but not Eso2 tumors. Induction of T-reg in Pan02 mice is blocked by systemic injection of an anti-TGF-beta antibody. If Rag(-/-) mice are instead reconstituted with naive CD4(+)25(-) T cells expressing a mutated TGF-beta receptor, induction of Foxp3(+) T-reg in Pan02 bearing mice is blocked. Collectively, these observations further support the role or TGF-beta in the induction of T-reg in pancreas adenocarcinoma.