Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Cell Rep. 2022 Nov 1;41(5):111582. doi: 10.1016/j.celrep.2022.111582.
In "healthy" tumor cells, phosphatidylserine (PS) is predominately localized in the inner plasma membrane leaflet. During apoptosis, PS relocates to the outer leaflet. Herein, we established PS tumor models with tumor cells lacking PS flippase component CDC50A, constantly exposing PS but alive. PS tumors developed bigger than wild-type (WT) tumors, featuring M2 polarized tumor-associated macrophages (TAMs) and fewer tumor-antigen-specific T cells. The PS receptor TIM-3 is responsible for PS recognition. Employing an opposite tumor model, PS, with tumor cells lacking the PS scramblase Xkr8 and unable to expose PS during otherwise normal apoptosis, we find that the accumulated apoptotic tumor cells produce and release cyclic GAMP (cGAMP) to immune cells to activate the STING pathway, leading to TAM M1 polarization, suppressed interleukin (IL)-10 secretion, and natural killer (NK) cell cytotoxicity. Silencing Xkr8 in vivo by either short hairpin RNA (shRNA) or small interfering RNA (siRNA) to achieve a PS externalization blockade provides robust therapeutic anti-tumor efficiency.
在“健康”的肿瘤细胞中，磷脂酰丝氨酸（PS）主要定位于质膜内层叶。在细胞凋亡过程中，PS 重新分布到外层叶。在此，我们建立了 PS 肿瘤模型，肿瘤细胞缺乏 PS 翻转酶成分 CDC50A，持续暴露 PS 但存活。PS 肿瘤比野生型（WT）肿瘤更大，其特征是 M2 极化的肿瘤相关巨噬细胞（TAM）和更少的肿瘤抗原特异性 T 细胞。PS 受体 TIM-3 负责 PS 的识别。采用相反的肿瘤模型，PS 肿瘤细胞缺乏 PS scramblase Xkr8，在正常凋亡过程中无法暴露 PS，我们发现积累的凋亡肿瘤细胞产生并释放环鸟苷酸-腺苷酸（cGAMP）到免疫细胞中，激活 STING 途径，导致 TAM M1 极化，抑制白细胞介素（IL）-10 分泌和自然杀伤（NK）细胞细胞毒性。通过短发夹 RNA（shRNA）或小干扰 RNA（siRNA）在体内沉默 Xkr8 以实现 PS 外化阻断，可提供强大的抗肿瘤治疗效率。
