The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis.
The small molecule TGF-β signaling inhibitor SM16 synergizes with agonistic OX40 antibody to suppress established mammary tumors and reduce spontaneous metastasis.
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DOI：
10.1007/s00262-011-1119-y
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发表时间：
2012-04
影响因子：
5.8
通讯作者：
Akporiaye, Emmanuel T.
中科院分区：
文献类型：
--
作者：
Garrison, Kendra;Hahn, Tobias;Lee, Wen-Cherng;Ling, Leona E.;Weinberg, Andrew D.;Akporiaye, Emmanuel T.
有效的肿瘤免疫治疗可能不仅需要激活抗肿瘤效应细胞，还需要取消肿瘤介导的免疫抑制。细胞因子转化生长因子-β在肿瘤微环境中经常升高，是一种强有力的免疫抑制剂和肿瘤转移的促进剂。OX40(CD134)是肿瘤坏死因子-α受体超家族的一员，用激发型抗体(抗OX40)连接可增强T细胞的效应功能、扩增和存活。在这项研究中，我们观察了小分子转化生长因子-β信号抑制剂SM16联合抗OX40在免疫原性差、高转移、转化生长因子-β分泌的4T1乳腺肿瘤模型中的治疗效果和抗肿瘤免疫反应。我们的数据显示，SM16与抗OX40具有协同作用，对已建立的原发肿瘤具有强大的抗肿瘤作用，肿瘤大小减少79%，转移肺结节数量减少95%，治愈率为38%。这一积极的治疗结果与肿瘤浸润性激活的CD8+T细胞增加3.2倍，CD4+和CD8+T细胞的总体积累以及肿瘤特异性效应T细胞反应的增加有关。体内CD4+和CD8+T细胞耗尽后的治疗效果完全消失，提示SM16+抗OX40治疗的抗肿瘤效果依赖于T细胞。肿瘤治愈的小鼠能够拒绝肿瘤的再攻击，并表现出显著的肿瘤特异性外周记忆干扰素-γ反应。综上所述，这些数据表明，将转化生长因子-β信号抑制剂与抗氧磷脂40结合是治疗转移性乳腺癌的一种可行的方法。
Effective tumor immunotherapy may require not only activation of anti-tumor effector cells, but also abrogation of tumor-mediated immunosuppression. The cytokine, TGF-β, is frequently elevated in the tumor microenvironment and is a potent immunosuppressive agent and promoter of tumor metastasis. OX40 (CD134) is a member of the TNF-α receptor superfamily and ligation by agonistic antibody (anti-OX40) enhances effector function, expansion and survival of activated T cells. In this study, we examined the therapeutic efficacy and anti-tumor immune response induced by the combination of a small molecule TGF-β signaling inhibitor, SM16, plus anti-OX40 in the poorly immunogenic, highly metastatic, TGF-β-secreting 4T1 mammary tumor model. Our data show that SM16 synergizes with anti-OX40 to elicit a potent anti-tumor effect against established primary tumors, with a 79% reduction in tumor size, a 95% reduction in the number of metastatic lung nodules and a cure rate of 38%. This positive treatment outcome was associated with a 3.2-fold increase of tumor-infiltrating, activated CD8+ T cells, an overall accumulation of CD4+ and CD8+ T cells, and an increased tumor-specific effector T cell response. Complete abrogation of the therapeutic effect in vivo following depletion of CD4+ and CD8+ T cells, suggests that the anti-tumor efficacy of SM16 + anti-OX40 therapy is T cell dependent. Mice that were cured of their tumors were able to reject tumor re-challenge and manifested a significant tumor-specific peripheral memory IFN-γ response. Taken together, these data suggest that combining a TGF-β signaling inhibitor with anti-OX40 is a viable approach for treating metastatic breast cancer.
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DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G
影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
8.8
作者：
Krasagakis, K;Tholke, D;Farthmann, B;Eberle, J;Mansmann, U;Orfanos, C E
通讯作者：
Orfanos, C E
影响因子：
11.2
作者：
Gough, Michael J.;Ruby, Carl E.;Weinberg, Andrew D.
通讯作者：
Weinberg, Andrew D.