Increased Frequency of Suppressive Regulatory T Cells and T Cell-Mediated Antigen Loss Results in Murine Melanoma Recurrence
Increased Frequency of Suppressive Regulatory T Cells and T Cell-Mediated Antigen Loss Results in Murine Melanoma Recurrence
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DOI：
10.4049/jimmunol.1103822
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发表时间：
2012-07-15
影响因子：
4.4
通讯作者：
Fox, Bernard A.
中科院分区：
文献类型：
--
作者：
Jensen, Shawn M.;Twitty, Christopher G.;Fox, Bernard A.
使用免疫疗法对大型已建立肿瘤的治疗性治疗产生了很少有希望的结果。我们研究了肿瘤特异性CD 8（+）T细胞和肿瘤特异性CD 4（+）T细胞的过继转移是否会介导缺乏调节性T细胞的淋巴细胞减少性Rag 1（-/-）受体中的大型B16 BL 6-D5黑色素瘤消退。亚治疗剂量的TRP 1特异性TCR转基因Rag 1（-/-）CD 4（+）T细胞和gp 100特异性TCR转基因Rag 1（-/-）CD 8（+）T细胞联合过继转移到接受疫苗接种的淋巴细胞减少受者中，导致大的（100-400 mm 2）黑素瘤消退。同样的治疗策略在淋巴细胞充盈的野生型小鼠中无效。25%的小鼠（15/59）肿瘤复发（消退后15-180天）。复发性肿瘤色素脱失，gp 100（CD 8（+）T细胞靶向的表位）表达减少。与未显示疾病证据的小鼠相比，复发性黑色素瘤小鼠的CD 4（+）Foxp 3（+）TRP 1特异性T细胞增加。重要的是，来自复发性肿瘤小鼠的脾细胞能够抑制来自无肿瘤小鼠的脾细胞的体内治疗功效。这些数据表明，大的已建立的肿瘤可以通过肿瘤特异性CD 8（+）和CD 4（+）T细胞的组合来治疗。此外，复发性肿瘤表现出Ag表达降低，这伴随着治疗性肿瘤特异性CD 4（+）T细胞群转化为Foxp 3（+）CD 4（+）调节性T细胞群。免疫学杂志，2012，189：767-776。
Therapeutic treatment of large established tumors using immunotherapy has yielded few promising results. We investigated whether adoptive transfer of tumor-specific CD8(+) T cells, together with tumor-specific CD4(+) T cells, would mediate regression of large established B16BL6-D5 melanomas in lymphopenic Rag1(-/-) recipients devoid of regulatory T cells. The combined adoptive transfer of subtherapeutic doses of both TRP1-specific TCR transgenic Rag1(-/-) CD4(+) T cells and gp100-specific TCR transgenic Rag1(-/-) CD8(+) T cells into lymphopenic recipients, who received vaccination, led to regression of large (100-400 mm 2) melanomas. The same treatment strategy was ineffective in lymphoreplete wild-type mice. Twenty-five percent of mice (15/59) had tumors recur (15-180 d postregression). Recurrent tumors were depigmented and had decreased expression of gp100, the epitope targeted by the CD8(+) T cells. Mice with recurrent melanoma had increased CD4(+) Foxp3(+) TRP1-specific T cells compared with mice that did not show evidence of disease. Importantly, splenocytes from mice with recurrent tumor were able to suppress the in vivo therapeutic efficacy of splenocytes from tumor-free mice. These data demonstrate that large established tumors can be treated by a combination of tumor-specific CD8(+) and CD4(+) T cells. Additionally, recurrent tumors exhibited decreased Ag expression, which was accompanied by conversion of the therapeutic tumor-specific CD4(+) T cell population to a Foxp3(+) CD4(+) regulatory T cell population. The Journal of Immunology, 2012, 189: 767-776.