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 CD8+ regulatory T cells
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 CD8+ regulatory T cells
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DOI：
10.4049/jimmunol.177.2.896
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发表时间：
2006-07-15
影响因子：
4.4
通讯作者：
Mills, Kingston H. G.
中科院分区：
文献类型：
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作者：
Jarnicki, Andrew G.;Lysaght, Joanne;Mills, Kingston H. G.
我们检验了一种假设，即免疫系统未能根除肿瘤是由于肿瘤生长所产生的免疫抑制环境，而免疫抑制环境受肿瘤生长部位的影响。我们证明小鼠的T细胞对旁观者抗原的反应被生长的CT26肿瘤抑制。从生长中的肿瘤中提纯的T细胞表达IL-10、转化生长因子-β和Foxp3的mRNA。细胞内细胞因子染色显示高频率分泌IL-10的巨噬细胞、树突状细胞以及CD4(+)和CD8(+)T细胞渗入肿瘤。相反，在CT26肺转移的小鼠中，T细胞干扰素-γ的产生很弱，CD8(+)的CTL反应是检测不到的，并且在S.C.注射CT26细胞，但在抗IL-10和抗转化生长因子-β的存在下增强。与此一致的是，CD8(+)T细胞的去除消除了CTL反应，促进了S.C.的进展。肿瘤。然而，在肺模型中，CD8(+)T细胞的耗尽显著降低了肿瘤负担。此外，体内CD4(+)或CD25(+)T细胞的耗尽减少了S.C.的肿瘤负担。和肺模型，这与CD8(+)T细胞产生显著增加的干扰素-γ有关。这些发现表明，肿瘤的生长促进了CD4(+)调节性T细胞的诱导或募集，这些调节性T细胞分泌IL-10和转化生长因子-β，并抑制效应CD8(+)T细胞的反应。然而，表达IL-10和转化生长因子-β的CD8(+)T调节细胞也被肺的免疫抑制环境招募或激活，在那里它们可能抑制抗肿瘤免疫的诱导。
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-beta, 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-gamma production was weak and CD8(+) CTL responses were undetectable in mice with CT26 lung metastases and weak and transient following s.c. injection of CT26 cells, but were enhanced in the presence of anti-IL-10 and anti-TGF-beta. Consistent with this, removal of CD8(+) T cells abrogated CTL responses and promoted progression of the s.c. 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 s.c. and lung models, and this was associated with significantly enhanced IFN-gamma 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-beta and suppress effector CD8(+) T cell responses. However, CD8(+) T regulatory cells expressing IL-10 and TGF-beta are also recruited or activated by the immunosuppressive environment of the lung, where they may suppress the induction of antitumor immunity.