Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

Huygens, Caroline; Liénart, Stéphanie; Dedobbeleer, Olivier; Stockis, Julie; Gauthy, Emilie; Coulie, Pierre G.; Lucas, Sophie

doi:10.1074/jbc.m115.655340

Cited by 24 publications

(19 citation statements)

References 51 publications

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“…encoding TCA intermediates in various solid tumors(LaGory & Giaccia 2016;Lee et al 2016;Pollard et al 2005). With reference to LAPTM4B, it has been extensively studied for genotyping studies associated with various cancers from serum as well as investigated for its expression in PBMCs and platelets(Cheng et al 2016;Gnatenko et al 2010;Huygens et al 2015;Ma et al 2015;Mo et al 2014).The current study confirmed the elevated expression of HIF-1α in peripheral blood of solid tumor patients as compared to normal healthy controls that have very low or negligible expression of HIF-1α. The stabilization of HIF-1α leads to the overexpression of hypoxia responsive genesthe MDR1.…”

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confidence: 74%

Peer Review #2 of "Co-expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumors (v0.1)"

2019

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Hypoxic tumor microenvironment is the major contributor of chemotherapy resistance in solid tumors. One of the key regulators of hypoxic responses within the cell is hypoxia inducible factor-1α that is involved in transcription of genes promoting cell survival and chemotherapy resistance. Multidrug resistance gene-1 (MDR1) and Lysosome-associated protein trans-membrane 4B-35 (LAPTM4B-35) are among those notable players which augment their responses to cellular hypoxia. MDR1 is the hypoxia responsive gene involved in multidrug resistance phenotype while LAPTM4B-35 is involved in chemotherapy resistance by stabilizing HIF-1α and overexpressing MDR1. Overexpression of HIF-1α, MDR1 and LAPTM4B has been associated with poor disease outcome in many cancers when studied individually at tissue level. However, accessibility of the tissues following the course of chemotherapy for ascertaining chemotherapy resistance is difficult and sometimes not clinically feasible. Therefore, indication of hypoxic biomarkers in patient's blood can significantly alter the clinical outcome. Hence there is a need to identify a blood based marker to understand the disease progression. In the current study the expression of hypoxia associated chemotherapy resistance genes were studied in the peripheral blood lymphocytes of solid tumor patients and any potential correlation with disease progression were explored. The expression of HIF-1α, MDR1 and LAPTM4B was studied in blood of 72 breast, 42 ovarian, 32 colon and 21 prostate cancer patients through real time PCR analysis using delta CT (cycle threshold) method. The statistical scrutiny was executed through Fisher's Exact test and Spearmen Correlation method. There was 12-13 fold increased in expression of HIF-1α, 2 fold increased in MDR 1 and 13-14fold increased in LAPTM4B mRNA level in peripheral blood of breast, ovarian, prostate and colon cancer patients. In the current study there was an association of HIF-1α, MDR1 and LAPTM4B expression with advanced tumor stage, metastasis and chemotherapy treated group in breast, ovarian, prostate and colon cancer patients. The spearmen analysis also revealed a positive linear association among HIF-1α, MDR1 and LAPTM4B in all the studied cancer patients. The elevated expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of

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confidence: 74%

Peer Review #2 of "Co-expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumors (v0.1)"

2019

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“…LAPTM4B plays a number of oncogenic roles, and high levels of this protein are associated with poor prognosis in many types of cancers. LAPTM4B was recently identified as binding to GARP and serving as a negative regulator for TGF-b1 production in human Tregs (29). Tregs also express high levels of FAS molecules (Fas cell surface death receptor, also known as APO-1/CD95), which play an important role in CD95L-mediated apoptosis (30).…”

Section: Electronic Sorting Of Foxp3mentioning

confidence: 99%

Electronic Sorting of Immune Cell Subpopulations Based on Highly Plastic Genes

Wang

Han

2016

The Journal of Immunology

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Immune cells are highly heterogeneous and plastic with regard to gene expression and cell phenotype. In this study, we categorized genes into those with low and high gene plasticity, and those categories revealed different functions and applications. We proposed that highly plastic genes could be suited for the labeling of immune cell subpopulations; thus, novel immune cell subpopulations could be identified by gene plasticity analysis. For this purpose, we systematically analyzed highly plastic genes in human and mouse immune cells. In total, 1,379 human and 883 mouse genes were identified as being extremely plastic. We also expanded our previous immunoinformatic method, electronic sorting, which surveys big data to perform virtual analysis. This approach used correlation analysis and took dosage changes into account, which allowed us to identify the differentially expressed genes. A test with human CD4+ T cells supported the method’s feasibility, effectiveness, and predictability. For example, with the use of human nonregulatory T cells, we found that FOXP3hiCD4+ T cells were highly expressive of certain known molecules, such as CD25 and CTLA4, and that this process of investigation did not require isolating or inducing these immune cells in vitro. Therefore, the sorting process helped us to discover the potential signature genes or marker molecules and to conduct functional evaluations for immune cell subpopulations. Finally, in human CD4+ T cells, 747 potential immune cell subpopulations and their candidate signature genes were identified, which provides a useful resource for big data–driven knowledge discoveries.

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“…Previous studies have proven that GARP is necessary for Tregs to activate latent TGF-β1 [ 17 – 18 ]. Thus, we explored whether GARP is also expressed on MSCs and whether it is important for MSCs to inhibit T cells through activating latent TGF-β1.…”

Section: Resultsmentioning

confidence: 99%

Mesenchymal stem cells inhibit T cell activation by releasing TGF-β1 from TGF-β1/GARP complex

et al. 2017

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Intervention with mesenchymal stem cells (MSCs) reveals a promising therapeutic tool to treat transplantation and autoimmune disease due to their immunoregulation capability. But the mechanisms of action are not fully investigated yet. Transforming growth factor-β1 (TGF-β1) exhibit multiple effects in migration, differentiation, and immunomodulation of MSCs. Glycoprotein A repetitions predominant (GARP) is an important marker of activated Treg (regulatory T cells). GARP binds latent TGF-β1 to regulate its activation, which is the indispensable step in Treg suppressing effector T cells. So far we don’t know whether GARP present on MSCs and its association with MSCs function. Our study show that MSCs express GARP which binds latent TGF-β1 on their cell surface. We also found that TGF-β1+/− MSCs produce less TGF-β1 and exhibit reduced capacity in inhibiting T cells. When TGF-β1 signaling pathway was blocked, MSCs show decreased activity in inhibiting T cells.Importantly, silencing GARP expression distinctively damaged the capacity of MSCs to inhibit IFN-γ production. These findings indicated the expression of GARP on MSCs and its functionality in activating LAP, thus demonstrating GARP as a novel biomarker and new target to improve the therapeutic efficacy of MSCs.

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Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

Cited by 24 publications

References 51 publications

Peer Review #2 of "Co-expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumors (v0.1)"

Peer Review #2 of "Co-expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumors (v0.1)"

Electronic Sorting of Immune Cell Subpopulations Based on Highly Plastic Genes

Mesenchymal stem cells inhibit T cell activation by releasing TGF-β1 from TGF-β1/GARP complex

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