The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

Moffett, Howell F.; Cartwright, Adam N.R.; Kim, Hye-Jung; Godec, Jernej; Pyrdol, Jason W.; Äijö, Tarmo; Martínez, Gustavo; Rao, Anjana; Lü, Jun; Golub, Todd R.; Cantor, Harvey; Sharpe, Arlene H.; Novina, Carl D.; Wucherpfennig, Kai W.

doi:10.1038/ni.3755

Cited by 66 publications

(64 citation statements)

References 65 publications

(75 reference statements)

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“…Although MIR31HG outlier profiles were shown to be both cancer‐specific and cancer cell‐intrinsic, we cannot exclude the possibility that the noncancerous tumor compartment may contribute to MIR31HG expression in some cases. Recently, it was shown that miR‐31‐5p expression in T cells increased during exposure to type I interferons . However, our analyses indicated that the prognostic value of MIR31 was independent of the level of CTL infiltration, and combination of the two markers identified a patient subgroup with a particularly poor survival.…”

Section: Discussionmentioning

confidence: 55%

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Eide

Eilertsen

Sveen

2019

Intl Journal of Cancer

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Elevated miR‐31 expression is associated with poor outcome in colorectal cancer (CRC). Whether the prognostic information is independent of known molecular subgroups and gene expression‐based consensus molecular subtypes (CMS) is currently unknown. To investigate this, we analyzed nearly 2000 CRC biopsies and preclinical models. The expression of miR‐31‐5p and its host transcript, long noncoding RNA MIR31HG , was strongly correlated (Spearman's ρ > 0.80). MIR31HG outlier expression was observed in 158/1265 (12%) of pCRCs and was associated with depletion of CMS2‐canonical subgroup (odds ratio = 0.21 [0.11–0.35]) and shorter relapse‐free survival (RFS) in multivariable analysis (adjusted hazard ratio = 2.2 [1.6–3.0]). For stage II disease, 5‐year RFS for patients with MIR31HG outlier status was 49% compared to 77% for those with normal‐like expression. MIR31HG outlier status was associated with inferior outcome also within clinical high risk groups and within the poor prognostic CMS4‐mesenchymal gene expression subtype specifically. Preclinical models with MIR31HG outlier expression were characterized by reduced expression of MYC targets as well as elevated epithelial‐mesenchymal transition, TNF‐α/NFκB, TGF‐β, and IFN‐α/γ gene expression signatures, indicating cancer cell‐intrinsic properties resembling the CMS4 subgroup—associations which were recapitulated in patient biopsies. Moreover, the prognostic value of MIR31HG outlier status was independent of cytotoxic T lymphocyte and fibroblast infiltration. We here present evidence that MIR31HG expression provides clinical stratification beyond major gene expression phenotypes and tumor immune and stromal cell infiltration and propose a model where increased expression is an indicator of a cellular state conferring intrinsic invasive and/or immuno‐evasive capabilities.

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Section: Discussionmentioning

confidence: 55%

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Eide

Eilertsen

Sveen

2019

Intl Journal of Cancer

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“…As a result, miRNAs can have diverse effects based on the cell type and cell state examined (Lu et al, 2015). Although there has been considerable effort to understand the role of specific miRNAs in the immune system and, to a lesser extent, in T cells (Moffett et al, 2017), there is little information about the role of specific miRs in T EX cells.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155

et al. 2018

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SUMMARY Persistent viral infections and tumors drive development of exhausted T (TEX) cells. In these settings, TEX cells establish an important host-pathogen or host-tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of TEX cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal TEX cell subset. Transcriptional profiling identified coordinated control of cell signaling and transcription factor pathways, including the key AP-1 family member Fosl2. Overexpression of Fosl2 reversed the miR-155 effects, identifying a link between miR-155 and the AP-1 transcriptional program in regulating TEX cells. Thus, we identify a mechanism of miR-155 regulation of TEX cells and a key role for Fosl2 in T cell exhaustion.

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“…Through decades of investigations, thousands of miRNAs have been found in humans and animals, among which a notable proportion of miRNAs are found to be critical in the pathogenesis of various diseases, including cardiovascular diseases [9,10,11,12,13,14]. Moreover, some circulating miRNAs predominantly express in CAD patients [15,16].…”

Section: Introductionmentioning

confidence: 99%

miR-126 in Peripheral Blood Mononuclear Cells Negatively Correlates with Risk and Severity and is Associated with Inflammatory Cytokines as well as Intercellular Adhesion Molecule-1 in Patients with Coronary Artery Disease

Zhang²

2018

Cardiology

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Objectives: The aim of this study was to evaluate the association of miR-126 with risk and severity of coronary artery disease (CAD) as well as its correlation with inflammatory cytokines and endothelial related proteins. Methods: In total, 215 patients suspected of CAD who underwent coronary angiography were enrolled in this case control study and were divided into a CAD group (n = 119) and control group (n = 96). miR-126 relative expression was assessed by real-time polymerase chain reaction. Results: The relative expression of miR-126 decreased in CAD patients compared to controls (p < 0.001), and the receiver operating characteristic curve showed a good diagnostic value of miR-126 for CAD risk with an area under the curve of 0.801 (95% CI 0.740-0.861). Additionally, miR-126 was negatively correlated with high-sensitivity C-reactive protein levels (p < 0.001) and reversely associated with TNF-α (p = 0.008) and IL-6 (p < 0.001) levels, while it was positively correlated with the IL-10 level (p < 0.001). In addition, miR-126 was negatively associated with intercellular adhesion molecule-1 (ICAM-1) levels (p = 0.001), and no association of miR-126 with vascular endothelial growth factor was detected (p = 0.142). Meanwhile, the miR-126 relative level was negatively associated with the Gensini score (p < 0.001). Conclusions: Peripheral blood mononuclear cell miR-126 predicts risk and severity and correlates with inflammatory cytokines as well as ICAM-1 in patients with CAD.

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The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

Cited by 66 publications

References 65 publications

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Long noncoding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell‐intrinsic properties

Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155

miR-126 in Peripheral Blood Mononuclear Cells Negatively Correlates with Risk and Severity and is Associated with Inflammatory Cytokines as well as Intercellular Adhesion Molecule-1 in Patients with Coronary Artery Disease

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