MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade
MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade
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DOI：
10.1016/j.immuni.2016.01.024
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发表时间：
2016-03-15
期刊：
影响因子：
32.4
通讯作者：
Mellman, Ira
中科院分区：
文献类型：
--
作者：
Ebert, Peter J. R.;Cheung, Jeanne;Mellman, Ira
有丝分裂原活化蛋白激酶（MAPK）激酶（MEK）的靶向抑制可诱导Ras通路中携带活化突变的肿瘤消退，但很少导致肿瘤根除。尽管将MEK抑制与T细胞定向免疫疗法组合可能导致更持久的疗效，但T细胞应答本身至少部分依赖于MEK活性。我们在这里发现，MEK抑制确实可以深度阻断荷瘤小鼠中初始CD 8（+）T细胞的启动，但实际上增加了肿瘤内效应表型抗原特异性CD 8（+）T细胞的数量。MEK抑制保护肿瘤浸润性CD 8（+）T细胞免于由慢性TCR刺激驱动的死亡，同时保留细胞毒性活性。将MEK抑制与抗程序性死亡配体1（PD-L1）组合导致协同和持久的肿瘤消退，即使其中任一药剂单独仅适度有效。因此，尽管MAP激酶途径在T细胞功能的某些方面至关重要，但MEK靶向剂可以与T细胞依赖性免疫疗法相容。
Targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) can induce regression of tumors bearing activating mutations in the Ras pathway but rarely leads to tumor eradication. Although combining MEK inhibition with T-cell-directed immunotherapy might lead to more durable efficacy, T cell responses are themselves at least partially dependent on MEK activity. We show here that MEK inhibition did profoundly block naive CD8(+) T cell priming in tumor-bearing mice, but actually increased the number of effector-phenotype antigen-specific CD8(+) T cells within the tumor. MEK inhibition protected tumor-infiltrating CD8(+) T cells from death driven by chronic TCR stimulation while sparing cytotoxic activity. Combining MEK inhibition with anti-programmed death-ligand 1 (PD-L1) resulted in synergistic and durable tumor regression even where either agent alone was only modestly effective. Thus, despite the central importance of the MAP kinase pathway in some aspects of T cell function, MEK-targeted agents can be compatible with T-cell-dependent immunotherapy.