OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis.
OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis.
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DOI：
10.1084/jem.20082205
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发表时间：
2009-05-11
期刊：
影响因子：
--
通讯作者：
Houghton AN
中科院分区：
文献类型：
--
作者：
Hirschhorn-Cymerman D;Rizzuto GA;Merghoub T;Cohen AD;Avogadri F;Lesokhin AM;Weinberg AD;Wolchok JD;Houghton AN
CD 4 + Foxp 3+调节性T（T reg）细胞的扩增和募集是生长肿瘤逃避免疫消除的机制。除了效应T细胞的扩增之外，成功的治疗干预可能需要减少肿瘤微环境中的T reg细胞。我们报告，烷化剂环磷酰胺（CTX）和靶向共刺激受体OX 40（OX 86）的激动剂抗体的联合使用提供了有效的抗肿瘤免疫力，能够使已建立的免疫原性差的B16黑色素瘤肿瘤消退。CTX给药导致肿瘤抗原释放，其在OX 86处理后显著增强抗肿瘤T细胞应答。我们证明了T reg细胞是联合治疗的重要细胞靶点。巧合的是，联合治疗导致外周中T reg细胞的扩增。然而，在肿瘤中，联合治疗诱导了显著的T reg细胞耗竭，伴随着效应CD 8 + T细胞的流入，导致有利的T效应细胞/T reg细胞比率。更仔细的检查显示，减少肿瘤内的T reg细胞水平导致过度活化和T reg细胞特异性凋亡。因此，我们建议CTX和OX 40的参与代表了一种新的和合理的化学免疫疗法。
Expansion and recruitment of CD4+ Foxp3+ regulatory T (T reg) cells are mechanisms used by growing tumors to evade immune elimination. In addition to expansion of effector T cells, successful therapeutic interventions may require reduction of T reg cells within the tumor microenvironment. We report that the combined use of the alkylating agent cyclophosphamide (CTX) and an agonist antibody targeting the co-stimulatory receptor OX40 (OX86) provides potent antitumor immunity capable of regressing established, poorly immunogenic B16 melanoma tumors. CTX administration resulted in tumor antigen release, which after OX86 treatment significantly enhanced the antitumor T cell response. We demonstrated that T reg cells are an important cellular target of the combination therapy. Paradoxically, the combination therapy led to an expansion of T reg cells in the periphery. In the tumor, however, the combination therapy induced a profound T reg cell depletion that was accompanied by an influx of effector CD8+ T cells leading to a favorable T effector/T reg cell ratio. Closer examination revealed that diminished intratumoral T reg cell levels resulted from hyperactivation and T reg cell–specific apoptosis. Thus, we propose that CTX and OX40 engagement represents a novel and rational chemoimmunotherapy.
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影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
募集高危险性CD8（+）T细胞的潜在池募集到抗肿瘤免疫反应中。
DOI：
10.1084/jem.20042167
发表时间：
2005-05-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ercolini AM;Ladle BH;Manning EA;Pfannenstiel LW;Armstrong TD;Machiels JP;Bieler JG;Emens LA;Reilly RT;Jaffee EM
通讯作者：
Jaffee EM
在CD4+ CD25+ T细胞分数中，处于风险和最近发作的1型糖尿病患者的凋亡增加。
影响因子：
3.7
作者：
Glisic-Milosavljevic, Sanja;Waukau, Jill;Jailwala, Parthav;Jana, Srikanta;Khoo, Huoy-Jii;Albertz, Hope;Woodliff, Jeffrey;Koppen, Marilyn;Alemzadeh, Ramin;Hagopian, William;Ghosh, Soumitra
通讯作者：
Ghosh, Soumitra
影响因子：
5.4
作者：
Ghiringhelli, F;Larmonier, N;Martin, F
通讯作者：
Martin, F
影响因子：
20.3
作者：
Biagi, E;Dotti, G;Brenner, M
通讯作者：
Brenner, M