PDF(Pubmed)
Abstract：
The direction and magnitude of immune responses are critically affected when dead cells are disposed of. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8) promotes the engulfment of apoptotic normal and cancerous cells without inducing inflammation. We have previously reported that a certain proportion of the cancer cells express abundant MFG-E8, and that such expression is associated with the shorter survival of patients with esophageal cancer who had received chemotherapy before surgery. However, the influence of tumor-derived and systemically existing MFG-E8 on antitumor immune responses has not yet been fully investigated. Herein, we showed that CTL-dependent antitumor immune responses were observed in mice with no or decreased levels of systemic MFG-E8, and that such responses were enhanced further with the administration of anti-PD-1 antibody. In mice with decreased levels of systemic MFG-E8, the dominance of regulatory T cells in tumor-infiltrating lymphocytes was inverted to CD8+ T cell dominance. MFG-E8 expression by tumor cells appears to affect antitumor immune responses only when the level of systemic MFG-E8 is lower than the physiological status. We have also demonstrated in the clinical setting that lower levels of plasma MFG-E8, but not MFG-E8 expression in tumor cells, before the treatment was associated with objective responses to anti-PD-1 therapy in patients with non-small cell lung cancer. These results suggest that systemic MFG-E8 plays a critical role during the immunological initiation process of antigen-presenting cells to increase tumor-specific CTLs. Regulation of the systemic level of MFG-E8 might induce efficient antitumor immune responses and enhance the potency of anti-PD-1 therapy.
摘要：
当死细胞被处置时,免疫应答的方向和幅度受到严重影响。乳脂球-表皮生长因子-因子8（MFG-E8）促进凋亡的正常和癌细胞的吞噬而不引起炎症。我们以前曾报道过一定比例的癌细胞表达丰富的MFG-E8，并且这种表达与手术前接受化疗的食管癌患者的生存期较短有关。然而,肿瘤来源的和全身存在的MFG-E8对抗肿瘤免疫反应的影响尚未得到充分研究.在这里，我们表明,在全身MFG-E8水平未升高或降低的小鼠中观察到CTL依赖性抗肿瘤免疫应答,且此类应答随着抗PD-1抗体的施用而进一步增强.在全身性MFG-E8水平降低的小鼠中，调节性T细胞在肿瘤浸润淋巴细胞中的优势与CD8T细胞优势相反。只有当系统MFG-E8的水平低于生理状态时,肿瘤细胞的MFG-E8表达似乎才会影响抗肿瘤免疫应答。我们还在临床环境中证明，肿瘤细胞中血浆MFG-E8的表达水平较低，而不是MFG-E8表达水平较低。治疗前与非小细胞肺癌患者抗PD-1治疗的客观反应相关.这些结果表明，全身性MFG-E8在抗原呈递细胞的免疫启动过程中起关键作用，以增加肿瘤特异性CTL。MFG-E8的全身水平的调节可能诱导有效的抗肿瘤免疫应答并增强抗PD-1治疗的效力。
