CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4

Liao, Peng; Wang, Weichao; Kryczek, Ilona; Xiong, Li; Bian, Yingjie; Sell, Amanda; Wei, Shuang; Grove, Sara; Johnson, Jeffrey; Kennedy, Paul D.; Gijón, Miguel A.; Shah, Yatrik M.; Zou, Weiping

doi:10.1016/j.ccell.2022.02.003

Cited by 432 publications

(285 citation statements)

References 49 publications

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“…Therefore, it is crucial to enhance immune cells recognizing tumor cells. Recently, accumulating studies have proved that ferroptosis is related to immune regulation, such as, CD8(+) T cells can increase the anti-tumor effect by inducing ferroptosis 35 , 36 . CD8(+) T cells promote lipid peroxidation and ferroptosis by inhibiting the expression of SLC7A11 and SLC3A2 transporters by releasing interferon γ and reducing cystine uptake by tumor cells 7 .…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis-related lncRNA signature predicts the prognosis and immune microenvironment of hepatocellular carcinoma

Fang

Liu

Feng

et al. 2022

Sci Rep

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This study aimed to construct a ferroptosis-related lncRNA signature to probe the prognosis and immune infiltration of HCC patients. The Cancer Genome Atlas (TCGA) database was randomly divided into two parts, with two-thirds training and one-third testing sets. Univariate, multivariate, and least absolute selection operator (LASSO) Cox regression analyses were performed to establish a ferroptosis-related lncRNA signature. The prognostic signature was constructed by 6 ferroptosis-related lncRNAs (PCAT6, MKLN1-AS, POLH-AS1, LINC00942, AL031985.3, LINC00942) shows a promising clinical prediction value in patients with HCC. Patients with high-risk score indicated a poorer prognosis than patients with low-risk score were shown in the training set (p < 0.001) and testing set (p = 0.024). Principal component analysis (PCA) and nomogram were performed to verify the value of the prognostic signature. The area under curves (AUCs) for 1-, 3-, and 5-year survival rates were 0.784, 0.726, 0.699, respectively. Moreover, TCGA revealed that immune cell subpopulations and related functions, including cytolytic activity, MHC class I, type I and type II IFN response, were significantly different between the two risk groups. Immune checkpoints such as PDCD1, CTLA4, CD44, VTCN1 were also abnormally expressed between the two risk groups. This prognostic signature based on the ferroptosis-related lncRNAs may be promising for the clinical prediction of prognosis and immunotherapeutic responses in patients with HCC.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis-related lncRNA signature predicts the prognosis and immune microenvironment of hepatocellular carcinoma

Fang

Liu

Feng

et al. 2022

Sci Rep

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“…CD8 + T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients 69 .…”

Section: Discussionmentioning

confidence: 99%

Expression of ferroptosis-related gene correlates with immune microenvironment and predicts prognosis in gastric cancer

Song

Shu

2022

Sci Rep

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The study is to explore the role of ferroptosis-related genes (FRGs) in the occurrence and development of gastric cancer (GC), and to construct a new prognosis signature to predict the prognosis in GC. Clinical information and corresponding RNA data of GC patients were downloaded from TCGA and GEO databases. Consensus clustering was performed to identify new molecular subgroups. ESTIMATE, CIBERSORT, McpCounter and TIMER algorithm were used to analyze the infiltration of immune cells in two molecular subgroups. LASSO algorithm and multivariate Cox analysis were used to construct a prognostic risk signature. Functional analysis was conducted to elucidate the underlying mechanisms. Finally, the FRPGs were verified by Quantitative Real-Time PCR. We obtained 16 FRGs and divided GC patients into two subgroups by consistent clustering. Cluster C1 with a higher abundance of immune cell infiltration but lower probability in response to immunotherapy, it was reasonable to speculate that Cluster C1 was in accordance with the immune rejection type. Functional analysis showed that the biological process of DEGs in training cohort mainly included immune globulin, and human immune response mediated by circulating immune globulin. GSEA analysis showed that compared with Cluster C2, Cluster C1 showed lower expression in lipid metabolism. The nomogram combined with risk signature and clinical features can accurately predict the prognosis of GC patients. We identified two molecular subtypes, Clusters C1 and C2. In Cluster C1, patients with poor prognosis present with a hyperimmune status and low lipid metabolism, and we speculate that Cluster C1 was in accordance with the immune rejection type. The risk model based on FRPGs can accurately predict the prognosis of GC. These results indicated that ferroptosis is associated with TIME, and deserved considerable attention in determining immunotherapy treatment strategy for GC patients.

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“…Thus, targeting of LRP8, for example, by the development of LRP8/SELENOP neutralizing antibodies, may overcome the limitations of strategies that aim to directly inhibit GPX4 or other members of the selenocysteine metabolic network, which could be limited by extensive organ toxicity as demonstrated by mouse genetic studies ( 33 ). Additionally, given the recognition that GPX4 inhibition can also impair T-cell function ( 34 ), but also contribute to the CD8+ T-cell mediated cancer cell killing ( 35, 36 ), it is important to consider that immune cells, like CD8+ T-cells lack LRP8 expression. Thus, targeting LRP8 could critically impair GPX4 function in MYCN tumors or metastasis while sparing immune cells and could therefore be seen as a potent combinatorial strategy with immunotherapies.…”

Section: Discussionmentioning

confidence: 99%

Selenocysteine metabolism is a targetable vulnerability inMYCN-amplified cancers

Alborzy

Chen

Yildiz

et al. 2022

Preprint

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Understanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma.

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CD8+ T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4

Cited by 432 publications

References 49 publications

Ferroptosis-related lncRNA signature predicts the prognosis and immune microenvironment of hepatocellular carcinoma

Ferroptosis-related lncRNA signature predicts the prognosis and immune microenvironment of hepatocellular carcinoma

Expression of ferroptosis-related gene correlates with immune microenvironment and predicts prognosis in gastric cancer

Selenocysteine metabolism is a targetable vulnerability inMYCN-amplified cancers

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