CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine
CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine
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DOI：
10.4049/jimmunol.176.3.1750
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Ferrini, S
中科院分区：
文献类型：
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作者：
Comes, A;Rosso, O;Ferrini, S
IL-21 是一种 IL-2 样细胞因子，通过特定的 IL-21R 和 IL-2R γ 链发出信号。由于经过基因改造可分泌IL-21的TS/A乳腺癌细胞（TS/A-IL-21）在同基因小鼠中具有很强的免疫原性，因此我们分析了它们作为疫苗的应用。在携带 TS/A 亲代细胞 (pc) 微转移的小鼠中，接种经过辐射的 TS/A-IL-21 细胞疫苗可显着延长动物的寿命，但仅治愈 17% 的小鼠。治愈小鼠的脾细胞响应 TS/A-pc 的 gp70env Ag 的 AH1 表位的刺激，产生 CTL 活性并产生 IFN-γ。我们测试了低治疗结果是否可能是由于 TS/A-pc 肿瘤和引流淋巴结中存在 CD4(+)CD25(+) 调节性 T 细胞 (Treg) 造成的，以及 IL-21 是否对这些细胞有任何影响。事实上，CD4(+)CD25(+)细胞响应AH1肽的刺激，抑制免疫小鼠脾细胞产生IFN-γ。低浓度的IL-21（10 ng/ml）未能逆转同种异体MLR中CD4（+）CD25（+）细胞的抑制活性，而60 ng/ml的rIL-21部分恢复了应答T细胞增殖。 CD25(-)淋巴细胞上IL-21R的表达表明IL-21对CD25(+)细胞耗尽的小鼠可能更有效。通过单剂量抗 CD25 mAb 与 TS/A-IL-21 细胞疫苗联合消除 Treg 细胞，可以治愈 > 70% 的微转移小鼠，而单独使用抗 CD25 mAb 治疗则没有效果。成功的联合免疫疗法需要 NK 细胞、CD8(+) T 细胞和 IFN-γ。总之，基于 IL-21 的细胞疫苗对微转移的免疫治疗可通过消除 CD25(+) 细胞而得到强烈增强。
IL-21 is an IL-2-like cytokine, signaling through a specific IL-21R and the IL-2R gamma-chain. Because the TS/A mammary adenocarcinoma cells genetically modified to secrete IL-21 (TS/A-IL-21) are strongly immunogenic in syngeneic mice, we analyzed their application as vaccine. In mice bearing TS/A-parental cell (pc) micrometastases, vaccination with irradiated TS/A-IL-21 cells significantly increased the animal life span, but cured only 17% of mice. Spleen cells from cured mice developed CTL activity and produced IFN-gamma in response to stimulation by the AH1 epitope of the gp70env Ag of TS/A-pc. We tested whether the low therapeutic outcome might be due to CD4(+)CD25(+) regulatory T cells (Treg) present in TS/A-pc tumors and draining lymph nodes and whether IL-21 had any effect on these cells. Indeed, CD4(+)CD25(+) cells suppressed IFN-gamma production by splenocytes from immune mice in response to stimulation by the AH1 peptide. Low concentrations of IL-21 (10 ng/ml) failed to reverse the inhibitory activity of CD4(+)CD25(+) cells in an allogeneic MLR, whereas 60 ng/ml rIL-21 partially restored responder T cell proliferation. IL-21R expression on CD25(-) lymphocytes suggested that IL-21 could be more effective in mice depleted of CD25(+) cells. Depletion of Treg cells by a single dose of anti-CD25 mAb combined with TS/A-IL-21 cell vaccine cured > 70% of mice bearing micrometastases, whereas anti-CD25 mAb treatment alone had no effect. Successful combined immunotherapy required NK cells, CD8(+) T cells, and IFN-gamma. In conclusion, immunotherapy of micrometastases by an IL-21-based cellular vaccine is strongly potentiated by CD25(+) cell depletion.