Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy.
Mertk on tumor macrophages is a therapeutic target to prevent tumor recurrence following radiation therapy.
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DOI：
10.18632/oncotarget.11823
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发表时间：
2016-11-29
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影响因子：
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通讯作者：
Gough MJ
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作者：
Crittenden MR;Baird J;Friedman D;Savage T;Uhde L;Alice A;Cottam B;Young K;Newell P;Nguyen C;Bambina S;Kramer G;Akporiaye E;Malecka A;Jackson A;Gough MJ
放射治疗提供了一种在受控位置杀死大量癌细胞的方法，导致肿瘤特异性抗原和内源性佐剂的释放。然而，通过激活参与凋亡细胞识别和吞噬的途径，辐照癌细胞在巨噬细胞中产生抑制性表型。我们证明巨噬细胞特异性吞噬受体Mertk在放射治疗后的肿瘤巨噬细胞中上调。巨噬细胞上的Mertk结扎通过NF-kB p50上调导致抗炎细胞因子反应，这反过来限制了放射治疗后的肿瘤控制。我们证明，在免疫原性肿瘤中，Mertk的丢失足以允许放射治疗后的肿瘤治愈。然而，在免疫原性较差的肿瘤中，TGFb抑制也需要导致放射治疗后的肿瘤治愈。这些数据表明Mertk是一个高度特异性的靶标，它的缺失使肿瘤控制与放射治疗相结合。
Radiation therapy provides a means to kill large numbers of cancer cells in a controlled location resulting in the release of tumor-specific antigens and endogenous adjuvants. However, by activating pathways involved in apoptotic cell recognition and phagocytosis, irradiated cancer cells engender suppressive phenotypes in macrophages. We demonstrate that the macrophage-specific phagocytic receptor, Mertk is upregulated in macrophages in the tumor following radiation therapy. Ligation of Mertk on macrophages results in anti-inflammatory cytokine responses via NF-kB p50 upregulation, which in turn limits tumor control following radiation therapy. We demonstrate that in immunogenic tumors, loss of Mertk is sufficient to permit tumor cure following radiation therapy. However, in poorly immunogenic tumors, TGFb inhibition is also required to result in tumor cure following radiation therapy. These data demonstrate that Mertk is a highly specific target whose absence permits tumor control in combination with radiation therapy.