Suppression of antitumor immunity by IL-10 and TGF-β-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and …

AG Jarnicki, J Lysaght, S Todryk… - The journal of …, 2006 - journals.aai.org
The journal of immunology, 2006journals.aai.org
We examined the hypothesis that a failure of the immune system to eradicate tumors is due
to the immunosuppressive environment created by the growing tumor, which is influenced
by the site of tumor growth. We demonstrated that T cell responses to a bystander Ag in mice
were suppressed by a growing CT26 tumor. T cells purified from the growing tumor
expressed mRNA for IL-10, TGF-β, and Foxp3. Intracellular cytokine staining revealed a high
frequency of IL-10-secreting macrophages, dendritic cells, and CD4+ and CD8+ T cells …
Abstract
We examined the hypothesis that a failure of the immune system to eradicate tumors is due to the immunosuppressive environment created by the growing tumor, which is influenced by the site of tumor growth. We demonstrated that T cell responses to a bystander Ag in mice were suppressed by a growing CT26 tumor. T cells purified from the growing tumor expressed mRNA for IL-10, TGF-β, and Foxp3. Intracellular cytokine staining revealed a high frequency of IL-10-secreting macrophages, dendritic cells, and CD4+ and CD8+ T cells infiltrating the tumor. In contrast, T cell IFN-γ production was weak and CD8+ CTL responses were undetectable in mice with CT26 lung metastases and weak and transient following sc injection of CT26 cells, but were enhanced in the presence of anti-IL-10 and anti-TGF-β. Consistent with this, removal of CD8+ T cells abrogated CTL responses and promoted progression of the sc tumor. However, in the lung model, depletion of CD8+ T cells significantly reduced the tumor burden. Furthermore, depletion of CD4+ or CD25+ T cells in vivo reduced tumor burden in sc and lung models, and this was associated with significantly enhanced IFN-γ production by CD8+ T cells. These findings suggest that tumor growth facilitates the induction or recruitment of CD4+ regulatory T cells that secrete IL-10 and TGF-β and suppress effector CD8+ T cell responses. However, CD8+ T regulatory cells expressing IL-10 and TGF-β are also recruited or activated by the immunosuppressive environment of the lung, where they may suppress the induction of antitumor immunity.
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