Integrated analysis reveals the participation of IL4I1, ITGB7, and FUT7 in reshaping the TNBC immune microenvironment by targeting glycolysis

Xia, Yu; Wang, Zhi; Li, Xingrui; Gao, Qinglei

doi:10.1080/07853890.2021.1937694

Cited by 16 publications

(12 citation statements)

References 54 publications

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“…Integrin beta-7 has been suggested to play a role in high-risk multiple myeloma and overexpression of Integrin beta-7 has been associated with DNAhypomethylation [32]. In addition to its cell adhesion, migration and homing roles, Integrin beta-7 has also been suggested to participate in regulating the immune microenvironment as well as suppressing cell proliferation through the glycolysis/glucose metabolism pathway [33,34]. However, the exact role of Integrin beta-7 specifically in AML is unknown.…”

Section: Discussionmentioning

confidence: 99%

Integrated multiomic approach for identification of novel immunotherapeutic targets in AML

Köhnke

Liu²,

Haubner

et al. 2022

Biomark Res

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Background Immunotherapy of acute myeloid leukemia has experienced considerable advances, however novel target antigens continue to be sought after. To this end, unbiased approaches for surface protein detection are limited and integration with other data types, such as gene expression and somatic mutational burden, are poorly utilized. The Cell Surface Capture technology provides an unbiased, discovery-driven approach to map the surface proteins on cells of interest. Yet, direct utilization of primary patient samples has been limited by the considerable number of viable cells needed. Methods Here, we optimized the Cell Surface Capture protocol to enable direct interrogation of primary patient samples and applied our optimized protocol to a set of samples from patients with acute myeloid leukemia (AML) to generate the AML surfaceome. We then further curated this AML surfaceome to exclude antigens expressed on healthy tissues and integrated mutational burden data from hematologic cancers to further enrich for targets which are likely to be essential to leukemia biology. Finally, we validated our findings in a separate cohort of AML patient samples. Results Our protocol modifications allowed us to double the yield in identified proteins and increased the specificity from 54 to 80.4% compared to previous approaches. Using primary AML patient samples, we were able to identify a total of 621 surface proteins comprising the AML surfaceome. We integrated this data with gene expression and mutational burden data to curate a set of robust putative target antigens. Seventy-six proteins were selected as potential candidates for further investigation of which we validated the most promising novel candidate markers, and identified CD148, ITGA4 and Integrin beta-7 as promising targets in AML. Integrin beta-7 showed the most promising combination of expression in patient AML samples, and low or absent expression on healthy hematopoietic tissue. Conclusion Taken together, we demonstrate the feasibility of a highly optimized surfaceome detection method to interrogate the entire AML surfaceome directly from primary patient samples and integrate this data with gene expression and mutational burden data to achieve a robust, multiomic target identification platform. This approach has the potential to accelerate the unbiased target identification for immunotherapy of AML.

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Section: Discussionmentioning

confidence: 99%

Integrated multiomic approach for identification of novel immunotherapeutic targets in AML

Köhnke

Liu²,

Haubner

et al. 2022

Biomark Res

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“…A recent study has pointed out that instead of IDO1, interleukin 4 induced 1 (IL4I1) is the novel and the main Trp‐catabolic enzyme in glioma and chronic lymphocytic leukemia, which explains the major reason why the clinical trials of IDO1 inhibitors are a failure 16 . Previous studies have also shown that IL4I1 is a crucial player in the immunosuppressive TME, which promotes the progression of breast cancer, ovarian cancer, melanoma, and colon cancer 17–22 . IL4I1 acts as the main regulator of Trp/AHR signaling and promotes the immune evasion of several cancer types, underscoring its significance as a key drug target.…”

Section: Introductionmentioning

confidence: 99%

Thymol targeting interleukin 4 induced 1 expression reshapes the immune microenvironment to sensitize the immunotherapy in lung adenocarcinoma

Li,

Shi,

Wang

et al. 2023

MedComm

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Immune checkpoint blockades are the most promising therapy in lung adenocarcinoma (LUAD). However, the response rate remains limited, underscoring the urgent need for effective sensitizers. Interleukin 4 induced 1 (IL4I1) is reported to have immunoinhibitory and tumor‐promoting effects in several cancers. However, the targetable value of IL4I1 in sensitizing the immunotherapy is not clear, and there is a lack of effective small molecules that specifically target IL4I1. Here, we show that silencing IL4I1 significantly remodels the immune microenvironment via inhibiting aryl hydrocarbon receptor (AHR) signaling, thereby enhancing the efficacy of anti‐PD‐1 antibody in LUAD, which suggests that IL4I1 is a potential drug target for the combination immunotherapy. We then identify thymol as the first small molecule targeting IL4I1 transcription through a drug screening. Thymol inhibits the IL4I1 expression and blocks AHR signaling in LUAD cells. Thymol treatment restores the antitumor immune response and suppresses the progression of LUAD in an orthotopic mouse model. Strikingly, the combination treatment of thymol with anti‐PD‐1 antibody shows significant tumor regression in LUAD mice. Thus, we demonstrate that thymol is an effective small molecule to sensitize the PD‐1 blockade in LUAD via targeting IL4I1, which provides a novel strategy for the immunotherapy of LUAD.

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“…Xu et al. confirmed that FUT7, IL4I1, and ITGB7 could remodel the glucose metabolism to strengthen the immunotherapy effect ( 39 ). The pivotal glycan-binding proteins, including selectins, singles, and galectins, are important orchestrators in regulating the immune response in tumor metastasis ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Tumor Glycosylation Characteristics and Implications for Immune Checkpoint Inhibitor’s Efficacy for Breast Cancer

Han

et al. 2022

Front. Immunol.

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The alterations of glycosylation, which is a common post-translational modification of proteins, have been acknowledged as key events in breast cancer (BC) oncogenesis and progression. The aberrant expression of glycosyltransferases leads to aberrant glycosylation patterns, posing the diagnostic potential in BC outcomes. The present study aims to establish a glycosyltransferase-based signature to predict BC prognosis and response to immune checkpoint inhibitors. We firstly screened 9 glycosyltransferase genes from The Cancer Genome Atlas (TCGA) database and accordingly established a glyco-signature for predicting the prognosis in BC patients. Patients with BC were successfully divided into high-risk and low-risk groups based on the median cutoff point for risk scores in this signature. Next, the combinational analyses of univariate and multivariate Cox regression, Kaplan–Meier, and receiver operating characteristic (ROC) curves were used to prove that this glyco-signature possessed excellent predictive performance for prognosis of BC patients, as the high-risk group possessed worse outcomes, in comparison to the low-risk group. Additionally, the Gene Set Enrichment Analysis (GSEA) and immunologic infiltration analysis were adopted and indicated that there was a more immunosuppressive state in the high-risk group than that in the low-risk group. The clinical sample validation verified that glycosyltransferase genes were differentially expressed in patients in the low- and high-risk groups, while the biomarkers of antitumor M1 macrophages were increased and N-glycosyltransferase STT3A decreased in the low-risk group. The final in vitro assay showed that the silencing of STT3A suppressed the proliferation and migration of BC cells. Collectively, our well-constructed glyco-signature is able to distinguish the high- and low-risk groups and accordingly predict BC prognosis, which will synergistically promote the prognosis evaluation and provide new immunotherapeutic targets for combating BC.

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Integrated analysis reveals the participation of IL4I1, ITGB7, and FUT7 in reshaping the TNBC immune microenvironment by targeting glycolysis

Cited by 16 publications

References 54 publications

Integrated multiomic approach for identification of novel immunotherapeutic targets in AML

Integrated multiomic approach for identification of novel immunotherapeutic targets in AML

Thymol targeting interleukin 4 induced 1 expression reshapes the immune microenvironment to sensitize the immunotherapy in lung adenocarcinoma

Analysis of Tumor Glycosylation Characteristics and Implications for Immune Checkpoint Inhibitor’s Efficacy for Breast Cancer

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