Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis
Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis
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DOI：
10.1158/0008-5472.can-16-1308
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发表时间：
2016-11-01
期刊：
影响因子：
11.2
通讯作者：
Conejo-Garcia, Jose R.
中科院分区：
文献类型：
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作者：
Allegrezza, Michael J.;Rutkowski, Melanie R.;Conejo-Garcia, Jose R.
靶向治疗对肿瘤免疫的影响似乎是矛盾的，而且人们对其了解甚少。在这里，我们表明，MEK抑制剂曲美替尼废除了从人或小鼠髓系祖细胞的单核细胞髓源性抑制细胞（mMDSC）的精氨酸驱动的扩增。MEK抑制也减少了肿瘤细胞产生的mMDSC趋化因子骨桥蛋白。总之，这些作用减少了mMDSC在荷瘤宿主中的积累，限制了KRas驱动的乳腺肿瘤的生长，即使曲美替尼在很大程度上未能直接抑制肿瘤细胞增殖。因此，曲美替尼通过一种需要CD8（+）T细胞的机制阻止体内肿瘤进展，这是自相矛盾的，因为该药物报告了抑制效应淋巴细胞的能力。与我们的观察结果一致，肿瘤来源的mMDSC的过继转移逆转了曲美替尼控制肿瘤生长的能力。总的来说，我们的工作表明，曲美替尼对免疫细胞的影响可以部分解释其有效性，而不是其对肿瘤细胞本身的活性。更广泛地说，通过对MEK抑制剂如何对肿瘤起作用提供更深刻的见解，我们的研究结果扩展了它们的潜在用途，通常可以阻断MDSC的扩增，这种扩增广泛发生在癌症中，以驱动它们的生长和进展。
Targeted therapies elicit seemingly paradoxical and poorly understood effects on tumor immunity. Here, we show that the MEK inhibitor trametinib abrogates cytokine-driven expansion of monocytic myeloid-derived suppressor cells (mMDSC) from human or mouse myeloid progenitors. MEK inhibition also reduced the production of the mMDSC chemotactic factor osteopontin by tumor cells. Together, these effects reduced mMDSC accumulation in tumor-bearing hosts, limiting the outgrowth of KRas-driven breast tumors, even though trametinib largely failed to directly inhibit tumor cell proliferation. Accordingly, trametinib impeded tumor progression in vivo through a mechanism requiring CD8(+) T cells, which was paradoxical given the drug's reported ability to inhibit effector lymphocytes. Confirming our observations, adoptive transfer of tumor-derived mMDSC reversed the ability of trametinib to control tumor growth. Overall, our work showed how the effects of trametinib on immune cells could partly explain its effectiveness, distinct from its activity on tumor cells themselves. More broadly, by providing a more incisive view into how MEK inhibitors may act against tumors, our findings expand their potential uses to generally blockm MDSC expansion, which occurs widely in cancers to drive their growth and progression.