Calreticulin promotes immunity and type I interferon-dependent survival in mice with acute myeloid leukemia.
Calreticulin promotes immunity and type I interferon-dependent survival in mice with acute myeloid leukemia.
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DOI：
10.1080/2162402x.2016.1278332
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Kline J
中科院分区：
文献类型：
--
作者：
Chen X;Fosco D;Kline DE;Kline J
癌细胞暴露于特定的化疗药物或γ射线照射会诱导某种形式的细胞死亡，从而刺激小鼠的免疫反应。这种“免疫原性细胞死亡”需要钙网蛋白（CRT）易位到质膜，这已被证明可以促进癌细胞的吞噬作用。然而，目前尚不清楚CRT对癌细胞吞噬作用的影响是否足以单独影响肿瘤免疫。生成表达细胞表面 CRT 的急性髓系白血病 (AML) 细胞，以表征 CRT 激活肿瘤免疫反应的机制。在表达 CRT 的白血病小鼠中观察到对 AML 的有效免疫介导控制或排斥。 “CRT效应”最终依赖于T细胞，但树突状细胞（DC），特别是CD8α+ DC，也是必要的，这表明CRT可能直接作用于这些DC。表达 CRT 的 AML 细胞在体内对 DC 的吞噬作用稍微更敏感，但这种效应不太可能解释所观察到的强效免疫。 CRT 不会影响经典的 DC 成熟标志物，但会诱导 I 型干扰素 (IFN) 的表达，这对于其对生存的积极影响至关重要。总之，CRT 充当“危险信号”，促进宿主 I 型 IFN 反应，并与诱导有效的白血病特异性 T 细胞免疫相关。
Exposure of cancer cells to particular chemotherapeutic agents or γ-irradiation induces a form of cell death that stimulates an immune response in mice. This “immunogenic cell death” requires calreticulin (CRT) translocation to the plasma membrane, which has been shown to promote cancer cell phagocytosis. However, it remains unclear whether the effect of CRT on cancer cell phagocytosis is alone sufficient to affect tumor immunity. Acute myeloid leukemia (AML) cells expressing cell-surface CRT were generated in order to characterize the mechanism(s) through which CRT activates tumor immune responses. Potent immune-mediated control or rejection of AML was observed in mice with CRT-expressing leukemia. The “CRT effect” was ultimately T-cell dependent, but dendritic cells (DCs), and CD8α+ DCs in particular, were also necessary, indicating that CRT might act directly on these DCs. CRT-expressing AML cells were slightly more susceptible to phagocytosis by DCs in vivo, but this effect was unlikely to explain the potent immunity observed. CRT did not affect classical DC maturation markers, but induced expression of type I interferon (IFN), which was critical for its positive effect on survival. In conclusion, CRT functions as a “danger signal” that promotes a host type I IFN response associated with the induction of potent leukemia-specific T-cell immunity.