美国阿斯利康公司Dmitry I. Gabrilovich研究组发现，肿瘤中性粒细胞的铁死亡导致癌症的免疫抑制。2022年11月16日，《自然》杂志在线发表了这项成果。

研究人员表示，铁死亡是一种非凋亡形式的调节性细胞死亡，是由调节性氧化机制的失调引发的，最终导致多不饱和磷脂的大量过氧化。铁死亡诱导剂在体外杀死肿瘤细胞方面显示出相当大的有效性，但在实验性动物模型中却没有明显的成功，免疫缺陷小鼠是个明显的例外。这表明，人们对铁死亡对免疫细胞的影响仍然知之甚少。病理上被激活的中性粒细胞（PMN），被称为骨髓源性抑制细胞（PMN-MDSC），是抗肿瘤免疫的主要负面调节因素。

研究人员发现肿瘤微环境中的PMN-MDSC会自发地因铁死亡而死亡。虽然减少了PMN-MDSC的存在，但铁死亡会诱发含氧脂质的释放并限制人类和小鼠T细胞的活性。在免疫功能正常的小鼠中，通过遗传和药物抑制铁死亡作用可以废除PMN-MDSC的抑制活性，减少肿瘤的进展，并与免疫检查点阻断协同抑制肿瘤的生长。相比之下，在免疫功能正常的小鼠中诱导铁死亡会促进肿瘤的生长。因此，铁死亡是肿瘤微环境中PMN-MDSC的一种独特和可靶向的免疫抑制机制，可以通过药物调节来限制肿瘤的进展。

附：英文原文

Title: Ferroptosis of tumour neutrophils causes immune suppression in cancer

Author: Kim, Rina, Hashimoto, Ayumi, Markosyan, Nune, Tyurin, Vladimir A., Tyurina, Yulia Y., Kar, Gozde, Fu, Shuyu, Sehgal, Mohit, Garcia-Gerique, Laura, Kossenkov, Andrew, Gebregziabher, Bereket A., Tobias, John W., Hicks, Kristin, Halpin, Rebecca A., Cvetesic, Nevena, Deng, Hui, Donthireddy, Laxminarasimha, Greenberg, Andrew, Nam, Brian, Vonderheide, Robert H., Nefedova, Yulia, Kagan, Valerian E., Gabrilovich, Dmitry I.

Issue&Volume: 2022-11-16

Abstract: Ferroptosis is a non-apoptotic form of regulated cell death that is triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Ferroptosis inducers have shown considerable effectiveness in killing tumour cells in vitro, yet there has been no obvious success in experimental animal models, with the notable exception of immunodeficient mice1,2. This suggests that the effect of ferroptosis on immune cells remains poorly understood. Pathologically activated neutrophils (PMNs), termed myeloid-derived suppressor cells (PMN-MDSCs), are major negative regulators of anti-tumour immunity3,4,5. Here we found that PMN-MDSCs in the tumour microenvironment spontaneously die by ferroptosis. Although decreasing the presence of PMN-MDSCs, ferroptosis induces the release of oxygenated lipids and limits the activity of human and mouse T cells. In immunocompetent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSCs, reduces tumour progression and synergizes with immune checkpoint blockade to suppress the tumour growth. By contrast, induction of ferroptosis in immunocompetent mice promotes tumour growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSCs in the tumour microenvironment that can be pharmacologically modulated to limit tumour progression.

DOI: 10.1038/s41586-022-05443-0

Source: https://www.nature.com/articles/s41586-022-05443-0