Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer.
Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer.
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DOI：
10.1038/s41467-017-00728-9
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发表时间：
2017-09-19
影响因子：
16.6
通讯作者：
Loi S
中科院分区：
文献类型：
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作者：
Dushyanthen S;Teo ZL;Caramia F;Savas P;Mintoff CP;Virassamy B;Henderson MA;Luen SJ;Mansour M;Kershaw MH;Trapani JA;Neeson PJ;Salgado R;McArthur GA;Balko JM;Beavis PA;Darcy PK;Loi S
三阴性乳腺癌中肿瘤浸润淋巴细胞的存在与预后的改善相关。 Ras/MAPK 通路激活与三阴性乳腺癌中肿瘤浸润淋巴细胞水平显着降低相关，虽然 MEK 抑制可以促进肿瘤浸润淋巴细胞向肿瘤的募集，但在此我们表明，MEK 抑制会对早发性 T 细胞效应功能产生不利影响。我们证明，α-4-1BB 和 α-OX-40 T 细胞激动剂抗体可以缓解小鼠和人类 T 细胞中 MEK 抑制对 T 细胞的不利影响，从而增强体内抗肿瘤作用。该效应依赖于下游 p38/JNK 通路激活的增加。综上所述，我们的数据表明，尽管 Ras/MAPK 通路抑制可以增加肿瘤免疫原性，但对 T 细胞活性的负面影响在功能上也很重要。通过与 T 细胞免疫激动剂免疫疗法相结合，可以有效防止这种不良影响，从而产生优异的治疗效果。乳腺癌中的 MEK 抑制与肿瘤浸润淋巴细胞 (TIL) 的增加有关，然而，T 细胞功能需要 MAPK 活性。作者在此表明，激动剂免疫疗法可以增强 MEK 抑制后的 TIL 活性，从而产生协同治疗效果。
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy. MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.
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影响因子：
3.8
作者：
Huang, Gonghua;Shi, Lewis Zhichang;Chi, Hongbo
通讯作者：
Chi, Hongbo
T细胞共刺激和共抑制的分子机制。
DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
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作者：
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
32.4
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
通讯作者：
Mellman, Ira
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
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