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Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy.

ABSTRACT: 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^out tumor models with tumor cells lacking PS flippase component CDC50A, constantly exposing PS but alive. PS^out 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, PSⁱⁿ, 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.

SUBMITTER: Wang W

PROVIDER: S-EPMC9671066 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy.

Wang Weihong W Wu Shaoxian S Cen Zhanpeng Z Zhang Yixin Y Chen Yuang Y Huang Yixian Y Cillo Anthony R AR Prokopec Joshua S JS Quarato Giovanni G Vignali Dario A A DAA Stewart-Ornstein Jacob J Li Song S Lu Binfeng B Gong Yi-Nan YN

Cell reports 20221101 5

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<sup>out</sup> tumor models with tumor cells lacking PS flippase component CDC50A, constantly exposing PS but alive. PS<sup>out</sup> 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- ...[more]

PMID: 36323258

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Project description:ObjectivePhosphatidylserine exposure mediates platelet procoagulant function and regulates platelet life span. Apoptotic, necrotic, and integrin-mediated mechanisms have been implicated as intracellular determinants of platelet phosphatidylserine exposure. Here, we investigate (1) the role of mitochondrial events in platelet phosphatidylserine exposure initiated by these distinct stimuli and (2) the cellular interactions of the procoagulant platelet in vitro and in vivo.Approach and resultsKey mitochondrial events were examined, including cytochrome c release and inner mitochondrial membrane (IMM) disruption. In both ABT-737 (apoptotic) and agonist (necrotic)-treated platelets, phosphatidylserine externalization was temporally correlated with IMM disruption. Agonist stimulation resulted in rapid cyclophilin D-dependent IMM disruption that coincided with phosphatidylserine exposure. ABT-737 treatment caused rapid cytochrome c release, eventually followed by caspase-dependent IMM disruption that again closely coincided with phosphatidylserine exposure. A nonmitochondrial and integrin-mediated mechanism has been implicated in the formation of a novel phosphatidylserine-externalizing platelet subpopulation. Using image cytometry, this subpopulation is demonstrated to be the result of the interaction of an aggregatory platelet and a procoagulant platelet rather than indicative of a novel intracellular mechanism regulating platelet phosphatidylserine externalization. Using electron microscopy, similar interactions between aggregatory and procoagulant platelets are demonstrated in vitro and in vivo within a mesenteric vein hemostatic thrombus.ConclusionsPlatelet phosphatidylserine externalization is closely associated with the mitochondrial event of IMM disruption identifying a common pathway in phosphatidylserine-externalizing platelets. The limited interaction of procoagulant platelets and integrin-active aggregatory platelets identifies a potential mechanism for procoagulant platelet retention within the hemostatic thrombus.

Dataset Information

Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy.

Publications

Mobilizing phospholipids on tumor plasma membrane implicates phosphatidylserine externalization blockade for cancer immunotherapy.

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