Homeostatic proliferation plus regulatory T-Cell depletion promotes potent rejection of B16 melanoma
Homeostatic proliferation plus regulatory T-Cell depletion promotes potent rejection of B16 melanoma
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DOI：
10.1158/1078-0432.ccr-07-4696
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发表时间：
2008-05-15
影响因子：
11.5
通讯作者：
Gajewski, Thomas F.
中科院分区：
文献类型：
--
作者：
Kline, Justin;Brown, Ian E.;Gajewski, Thomas F.
目的：在一种临床相关的小鼠过继免疫治疗模型中，探讨通过体内平衡增殖和调节性T细胞(Treg)耗竭来逆转T细胞无能的抗肿瘤效果。实验设计：B16黑色素瘤细胞通过基因工程表达模型SIYRYYGL(SIY)抗原，以实现免疫监测。肿瘤特异性T细胞在肿瘤挑战野生型宿主中扩张，但变得反应迟钝。为了验证淋巴细胞减少诱导的动态平衡增殖是否可以逆转肿瘤诱导的T细胞无能，将全脾T细胞转移到淋巴细胞减少的RAG2(-1-)小鼠或对照P14/RAG2(-/-)小鼠中。测量肿瘤生长，并使用ELISPOT和SIY/K-b四聚体监测SIY特异性免疫反应。为了确定Treg缺失是否与体内平衡增殖协同作用，RAG2(-/-)小鼠接受完全或CD25缺失的T细胞，然后或之前接受B16 SIY攻击。结果：过继将全脾T细胞转移到RAG2(-/-)小鼠体内对B16的生长有中等程度的影响。SIY在荷瘤小鼠体内发生Treg扩增时，CD25(+)T细胞在过继转移前从总T细胞中耗尽。有趣的是，将CD25缺失的T细胞转移到RAG2(-1-)小鼠体内，在预防和短期移植前肿瘤环境中都能导致对B16黑色素瘤的有效排斥，并与维持T细胞效应器功能有关。采用临床适用的方法，野生型小鼠采用亚致死性全身照射，同样支持CD25缺失的T细胞转移的肿瘤排斥反应。结论：我们的结果表明，CD25缺失和体内平衡增殖相结合的方法支持了强大的抗肿瘤免疫反应--一种具有临床推广潜力的方法。
Purpose: To investigate the antitumor efficacy of T-cell anergy reversal through homeostatic proliferation and regulatory T-cell (Treg) depletion in a clinically relevant murine adoptive immunotherapy model.Experimental Design: B16 melanoma cells were engineered to express the model SIYRYYGL (SIY) antigen to enable immune monitoring. Tumor-specific T cells expanded in tumor-challenged wild-type hosts but became hyporesponsive. To examine whether lymphopenia-induced homeostatic proliferation could reverse tumor-induced T-cell anergy, total splenicTcells were transferred into lymphopenic RAG2(-1-) mice or control P14/RAG2(-/-) mice. Tumor growth was measured, and SIY-specific immune responses were monitored using ELISPOT and SIY/K-b tetramers. To determine whether Treg depletion could synergize with homeostatic proliferation, RAG2(-/-) mice received total or CD25-depleted T cells, followed or preceded by B16.SIY challenge. This approach was further investigated in wild-type mice lymphodepleted with sublethal total body irradiation.Results: Adoptive transfer of total splenic T cells into RAG2(-/-) mice moderately affected the growth rate of B16.SIY As Treg expansion occurred in tumor-bearing mice, CD25(+) T cells were depleted from totalTcells before adoptive transfer. Interestingly, transfer of CD25-depleted T cells into RAG2(-1-) mice resulted in potent rejection of B16 melanoma in both prophylactic and short-term preimplanted tumor settings and was associated with maintained T-cell effector function. Using a clinically applicable approach, wild-type mice were lymphodepleted using sublethal total body irradiation, which similarly supported tumor rejection upon transfer of CD25-depleted Tcells.Conclusions: Our results indicate that combined CD25 depletion and homeostatic proliferation support a potent antitumor immune response-an approach with potential for clinical translation.