目的:在胶质母细胞瘤(GBM)中积极探索免疫治疗以改善患者预后。肿瘤相关巨噬细胞(TAM)在GBM中是丰富的,并且利用它们的功能进行抗肿瘤免疫是令人感兴趣的。它们是受肿瘤微环境影响的塑料细胞,通过放化疗和它们自己的吞噬活性。的确,坏死细胞的吞噬促进了促炎(和抗肿瘤)功能,而凋亡细胞的吞噬通过红细胞增生促进了抗炎(和促肿瘤)功能.
方法:为了模拟放化疗对GBM微环境的影响,我们将人巨噬细胞暴露于体外处理的GBM细胞的上清液中。巨噬细胞来源于人单核细胞和来自患者切除的肿瘤的GBM细胞。将GBM细胞暴露于治疗相关剂量的照射和化疗。通过流式细胞术评估细胞凋亡和吞噬活性。
结果:巨噬细胞的吞噬活性增加,并且与产生上清液的凋亡GBM细胞的比例相关。是否会发生凋亡性肿瘤细胞的摄取将取决于有效胞吞作用相关受体的表达。的确,我们发现了与红细胞增多相关的受体,例如AXL,被上调了。
结论:我们表明,当暴露于通过放化疗处理的GBM细胞的上清液时,巨噬细胞吞噬活性增加。然而,由于红细胞增多相关受体上调,这种效应对于抗GBM免疫应答可能是有害的.我们推测,通过诱导GBM细胞凋亡,同时增加细胞凋亡受体的表达,放化疗对吞噬活性的影响可促进TAM的抗炎和促肿瘤功能.
Immunotherapy is actively explored in glioblastoma (GBM) to improve patient prognosis. Tumor-associated macrophages (TAMs) are abundant in GBM and harnessing their function for anti-tumor immunity is of interest. They are plastic cells that are influenced by the tumor microenvironment, by radio-chemotherapy and by their own phagocytic activity. Indeed, the engulfment of necrotic cells promotes pro-inflammatory (and anti-tumoral) functions while the engulfment of apoptotic cells promotes anti-inflammatory (and pro-tumoral) functions through efferocytosis.
To model the effect of radio-chemotherapy on the GBM microenvironment, we exposed human macrophages to supernatant of treated GBM cells in vitro. Macrophages were derived from human monocytes and GBM cells from patient-resected tumors. GBM cells were exposed to therapeutically relevant doses of irradiation and chemotherapy. Apoptosis and phagocytic activity were assessed by flow cytometry.
The phagocytic activity of macrophages was increased, and it was correlated with the proportion of apoptotic GBM cells producing the supernatant. Whether uptake of apoptotic tumor cells could occur would depend upon the expression of efferocytosis-associated receptors. Indeed, we showed that efferocytosis-associated receptors, such as AXL, were upregulated.
We showed that macrophage phagocytic activity increased when exposed to supernatant from GBM cells treated by radio-chemotherapy. However, as efferocytosis-associated receptors were up-regulated, this effect could be deleterious for the anti-GBM immune response. We speculate that by inducing GBM cell apoptosis in parallel to an increase in efferocytosis receptor expression, the impact of radio-chemotherapy on phagocytic activity could promote anti-inflammatory and pro-tumoral TAM functions.