Pan-cancer analysis combined with experimental validation revealed IL4I1 as an immunological and prognostic biomarker

Rao, Dean; Yu, Chengpeng; Wang, Tiantian; Sheng, Jiaqi; Lv, Enjun; Liang, Huifang; Huang, Wenjie; Dong, Hanhua

doi:10.1016/j.intimp.2022.109091

Cited by 7 publications

(5 citation statements)

References 33 publications

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“…New therapeutic strategies targeting TAMs have been anchored in interfering with cascade pathways, reconstituting TAMs with drugs or therapeutic genes, and depleting TAMs (12). Previous studies have indicated that IL4I1 could regulate the immune properties of OV (19), KIRC (23), and LIHC (22). Meanwhile, researchers found that the ectopic expression of IL4I1 on glioma cells can promote their migration ability (17).…”

Section: Discussionmentioning

confidence: 99%

“…Singlecell analysis showed that IL4I1 promotes the development of ovarian cancer (OV) and is a critical gene in the Riskscore (19). Some researchers have found that IL4I1, as a prognostic biomarker, augments tumor growth by reprogramming TME in melanoma, kidney renal clear cell carcinoma (KIRC), and liver hepatocellular carcinoma (LIHC), which is attributed to its association with the movement and recruitment of leukocytes (20)(21)(22)(23). Furthermore, IL4I1 expression has been detected in mesenchymal stromal cells of head-neck squamous cell carcinoma (HNSC) and contributes to immune response modulation and T-cell suppression (24).…”

Section: Introductionmentioning

confidence: 99%

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IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy

Ye,

Wang,

et al. 2024

Front. Immunol.

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BackgroundGlioma is the prevailing malignant intracranial tumor, characterized by an abundance of macrophages. Specifically, the infiltrating macrophages often display the M2 subtype and are known as tumor-associated macrophages (TAMs). They have a critical role in promoting the oncogenic properties of tumor cells. Interleukin-4-induced-1 (IL4I1) functions as an L-phenylalanine oxidase, playing a key part in regulating immune responses and the progression of various tumors. However, there is limited understanding of the IL4I1-mediated cross-talk function between TAMs and glioma cell in the glioma microenvironment.MethodsTCGA, GTEx, and HPA databases were applied to assess the IL4I1 expression, clinical characteristics, and prognostic value of pan-cancer. The link between IL4I1 levels and the prognosis, methylation, and immune checkpoints (ICs) in gliomas were explored through Kaplan–Meier curve, Cox regression, and Spearman correlation analyses. The IL4I1 levels and their distribution were investigated by single-cell analysis and the TIMER 2 database. Additionally, validation of IL4I1 expression was performed by WB, RT-qPCR, IHC, and IF. Co-culture models between glioma cells and M2-like macrophages were used to explore the IL4I1-mediated effects on tumor growth, invasion, and migration of glioma cells. Moreover, the function of IL4I1 on macrophage polarization was evaluated by ELISA, RT-qPCR, WB, and siRNA transfection.ResultsBoth transcriptome and protein levels of IL4I1 were increased obviously in various tumor types, and correlated with a dismal prognosis. Specifically, IL4I1 was implicated in aggressive progression and a dismal prognosis for patients with glioma. A negative association was noticed between the glioma grade and DNA promoter methylation of IL4I1. Enrichment analyses in glioma patients suggested that IL4I1 was linked to cytokine and immune responses, and was positively correlated with ICs. Single-cell analysis, molecular experiments, and in vitro assays showed that IL4I1 was significantly expressed in TAMs. Importantly, co-culture models proved that IL4I1 significantly promoted the invasion and migration of glioma cells, and induced the polarization of M2-like macrophages.ConclusionIL4I1 could be a promising immunotherapy target for selective modulation of TAMs and stands as a novel macrophage-related prognostic biomarker in glioma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy

Ye,

Wang,

et al. 2024

Front. Immunol.

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“…The discovery presented a hopeful tumor biomarker for forecasting the prognosis of lung adenocarcinoma and a potential target for treatment [ 38 ]. Studies have shown that IL4I1 has the capacity to function as both a marker and a focus for treatment [ 39 , 40 ]. NUSAP1 is linked to the development of different forms of cancers [ 41 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

A new prognostic model based on gamma-delta T cells for predicting the risk and aiding in the treatment of clear cell renal cell carcinoma

Wu,

Yao,

et al. 2024

Discov Onc

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Background ccRCC is the prevailing form of RCC, accounting for the majority of cases. The formation of cancer and the body's ability to fight against tumors are strongly connected to Gamma delta (γδ) T cells. Methods We examined and analyzed the gene expression patterns of 535 individuals diagnosed with ccRCC and 72 individuals serving as controls, all sourced from the TCGA-KIRC dataset, which were subsequently validated through molecular biology experiments. Results In ccRCC, we discovered 304 module genes (DEGRGs) that were ex-pressed differentially and linked to γδ T cells. A risk model for ccRCC was constructed using 13 differentially DEGRGs identified through univariate Cox and LASSO regression analyses, which were found to be associated with prognosis. The risk model exhibited outstanding performance in both the training and validation datasets. The comparison of immune checkpoint inhibitors and the tumor immune microenvironment between the high- and low-risk groups indicates that immunotherapy could lead to positive results for low-risk patients. Moreover, the inhibition of ccRCC cell proliferation, migration, and invasion was observed in cell culture upon knocking down TMSB10, a gene associated with different types of cancers. Conclusions In summary, we have created a precise predictive biomarker using a risk model centered on γδ T cells, which can anticipate clinical results and provide direction for the advancement of innovative targeted therapies.

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“…Similarly, IL4I1 mRNA expression is higher in patients with metastatic melanoma compared to those with primary melanoma [18]. In vitro, IL4I1 has been shown to promote the proliferation, migration and invasion of various tumor cell types [18,48], including ovarian cancer cells [49]. IL4I1 therefore presents a potential therapeutic target for ovarian cancer, while its expression, activity or metabolite levels may also serve as a biomarker for disease progression.…”

Section: Discussionmentioning

confidence: 99%

Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1

Grobben¹,

Ouden

Aguado³

et al. 2023

Cancers

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The molecular mechanisms contributing to immune suppression in ovarian cancer are not well understood, hampering the successful application of immunotherapy. Amino acid-metabolizing enzymes are known to contribute to the immune-hostile environment of various tumors through depletion of amino acids and production of immunosuppressive metabolites. We aimed to collectively evaluate the activity of these enzymes in high-grade serous ovarian cancer patients by performing targeted metabolomics on plasma and ascites samples. Whereas no indication was found for enhanced l-arginine or l-glutamine metabolism by immunosuppressive enzymes in ovarian cancer patients, metabolism of l-tryptophan by indoleamine 2,3-dioxygenase 1 (IDO1) was significantly elevated compared to healthy controls. Moreover, high levels of l-phenylalanine- and l-tyrosine-derived metabolites associated with interleukin 4 induced 1 (IL4I1) activity were found in ovarian cancer ascites samples. While l-tryptophan is a major substrate of both IDO1 and IL4I1, only its enhanced conversion into l-kynurenine by IDO1 could be detected, despite the observed activity of IL4I1 on its other substrates. In ascites of ovarian cancer patients, metabolite levels were higher compared to those in plasma, demonstrating the value of utilizing this fluid for biomarker identification. Finally, elevated metabolism of l-phenylalanine and l-tyrosine by IL4I1 correlated with disease stage, pointing towards a potential role for IL4I1 in ovarian cancer progression.

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Pan-cancer analysis combined with experimental validation revealed IL4I1 as an immunological and prognostic biomarker

Cited by 7 publications

References 33 publications

IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy

IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy

A new prognostic model based on gamma-delta T cells for predicting the risk and aiding in the treatment of clear cell renal cell carcinoma

Amino Acid-Metabolizing Enzymes in Advanced High-Grade Serous Ovarian Cancer Patients: Value of Ascites as Biomarker Source and Role for IL4I1 and IDO1

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