Chen Xiufen, Fosco Dominick, Kline Douglas E, Kline Justin
Department of Medicine, University of Chicago, Chicago, IL, USA.
Committee on Immunology, University of Chicago, Chicago, IL, USA.
Oncoimmunology. 2017 Jan 10;6(4):e1278332. doi: 10.1080/2162402X.2016.1278332. eCollection 2017.
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 , 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.
将癌细胞暴露于特定的化疗药物或γ射线会诱导一种细胞死亡形式，这种形式能在小鼠体内刺激免疫反应。这种“免疫原性细胞死亡”需要钙网蛋白（CRT）转位至质膜，研究表明这会促进癌细胞的吞噬作用。然而，CRT对癌细胞吞噬作用的影响是否足以单独影响肿瘤免疫仍不清楚。为了阐明CRT激活肿瘤免疫反应的机制，研究人员构建了表达细胞表面CRT的急性髓系白血病（AML）细胞。在患有表达CRT白血病的小鼠中观察到了强大的免疫介导的AML控制或排斥。“CRT效应”最终依赖于T细胞，但树突状细胞（DC），尤其是CD8α DC也是必需的，这表明CRT可能直接作用于这些DC。表达CRT的AML细胞对DC吞噬作用的敏感性略高，但这种效应不太可能解释所观察到的强大免疫力。CRT不影响经典DC成熟标志物，但诱导了I型干扰素（IFN）的表达，这对其对生存的积极作用至关重要。总之，CRT作为一种“危险信号”，促进了与强大的白血病特异性T细胞免疫诱导相关的宿主I型IFN反应。
