NUB1 and FAT10 Proteins as Potential Novel Biomarkers in Cancer: A Translational Perspective

Cancer increases the global disease burden substantially, but it remains a challenge to manage it. The search for novel biomarkers is essential for risk assessment, diagnosis, prognosis, prediction of treatment response, and cancer monitoring. This paper examined NEDD8 ultimate buster-1 (NUB1) and F-adjacent transcript 10 (FAT10) proteins as novel biomarkers in cancer. This literature review is based on the search of the electronic database, PubMed. NUB1 is an interferon-inducible protein that mediates apoptotic and anti-proliferative actions in cancer, while FAT10 is a ubiquitin-like modifier that promotes cancer. The upregulated expression of both NUB1 and FAT10 has been observed in various cancers. NUB1 protein binds to FAT10 non-covalently to promote FAT10 degradation. An overexpressed FAT10 stimulates nuclear factor-kappa β, activates the inflammatory pathways, and induces the proliferation of cancer. The FAT10 protein interacts with the mitotic arrest deficient 2 protein, causing chromosomal instability and breast tumourigenesis. FAT10 binds to the proliferating cell nuclear antigen protein and inhibits the DNA damage repair response. In addition, FAT10 involves epithelial–mesenchymal transition, invasion, apoptosis, and multiplication in hepatocellular carcinoma. Our knowledge about them is still limited. There is a need to further develop NUB1 and FAT10 as novel biomarkers.

The DNA sensors AIM2 and IFI16 are NET-binding SLE autoantigens

Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFNinducible innate sensors that form supramolecular assemblies along double-stranded DNA of various origins. Here, we identify the ALR Absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16 and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a proimmune context, finding that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE.

CyTOF Profiling of Zika and Dengue Virus-Infected Human Peripheral Blood Mononuclear Cells Identifies Phenotypic Signatures of Monotype Subsets and Upregulation of the Interferon-Inducible Protein CD169

Zika and dengue viruses are emergent arboviruses of great public health impact. Both viruses are responsible for important diseases, yet there is currently no vaccine or specific treatment available.

Overexpression of Interferon-Inducible Protein 16 Promotes Progression of Human Pancreatic Adenocarcinoma Through Interleukin-1β-Induced Tumor-Associated Macrophage Infiltration in the Tumor Microenvironment

Activation of inflammasomes has been reported in human pancreatic adenocarcinoma (PAAD); however, the expression pattern and functional role of inflammasome-related proteins in PAAD have yet to be identified. In this study, we systemically examined the expression and role of different inflammasome proteins by retrieving human expression data. Several genes were found to be differentially expressed; however, only interferon-inducible protein 16 (IFI16) expression was found to be adversely correlated with the overall survival of PAAD patients. Overexpression of IFI16 significantly promoted tumor growth, increased tumor size and weight in the experimental PAAD model of mice, and specifically increased the population of tumor-associated macrophages (TAMs) in the tumor microenvironment. Depletion of TAMs by injection of liposome clodronate attenuated the IFI16 overexpression-induced tumor growth in PAAD. In vitro treatment of conditioned medium from IFI16-overexpressing PAAD cells induced maturation, proliferation, and migration of bone marrow-derived monocytes, suggesting that IFI16 overexpression resulted in cytokine secretion that favored the TAM population. Further analysis suggested that IFI16 overexpression activated inflammasomes, thereby increasing the release of IL-1β. Neutralization of IL-1β attenuated TAM maturation, proliferation, and migration induced by the conditioned medium from IFI16-overexpressing PAAD cells. Additionally, knockdown of IFI16 could significantly potentiate gemcitabine treatment in PAAD, which may be associated with the reduced infiltration of TAMs in the tumor microenvironment. The findings of our study shed light on the role of IFI16 as a potential therapeutic target for PAAD.

POS0869 PREDICTIVE VALUE OF ANTI-INTERFERON-INDUCIBLE PROTEIN 16 ANTIBODIES FOR DIGITAL ULCERS OF SYSTEMIC SCLEROSIS

Background:Interferon-inducible protein 16 (IFI-16) is constitutively expressed in vascular endothelial cells and can inhibit the proliferation of human endothelial cells and the formation of capillary-like structures in vitro. Anti-IFI-16 antibodies were reported in 21%-29% of patients with systemic sclerosis (SSc) and were associated with digital vascular events in a few retrospective studies.Objectives:To evaluate the presence and the clinical implication of anti-IFI-16 antibodies in Chinese SSc cohort, focusing on the associations with vasculopathy indexes, and to investigate the predictive value of anti-IFI-16 antibodies for the development of digital ulcers (DUs) in SSc prospectively.Methods:Patients with SSc presenting to our center between July 2018 and September 2018 were prospectively enrolled. Serum from 42 SSc patients and 42 age- and sex-matched healthy controls were analyzed for anti-IFI-16 antibodies by enzyme-linked immunosorbent assay (ELISA), and was considered positive if the optical density (OD) value was above the mean OD of controls plus two standard deviations. Tissue immunofluorescence was used to evaluate the expression of IFI16 in skin biopsy samples obtained from SSc patients and normal controls. At baseline, nailfold video-capillaroscopy was performed to assess nailfold capillary density of SSc patients. Power Doppler ultrasound was used to grade finger pulp blood flow (0-no observed flow; 1-decreased flow; 2-normal flow), and to measure ulnar and radial artery blood flow and resistive index (RI). All patients were followed up for 6 months to see whether they experienced new onset or recurrent DUs. The association of anti-IFI-16 antibodies with DUs was analyzed using logistic regression.Results:Of the 42 SSc patients, 8 (19.0%) were positive for anti-IFI-16 antibodies. Immunofluorescence of skin biopsy samples from SSc patients exhibited enhanced staining of IFI-16 in the dermis, and colocalization with endothelial marker CD31. SSc patients who were positive for anti-IFI-16 antibodies showed higher ulnar artery RI at baseline (0.95±0.09 vs. 0.86±0.09, p=0.015), while no significant differences were found for other vascular parameters, nor for clinical or demographic profiles. Within 6-month follow-up, 14 (33.3%) patients experienced new-onset or recurrent DUs. Univariate logistic regression revealed the presence of DUs at enrollment (p=0.009), anti-IFI-16 antibody (p=0.012), finger pulp blood flow (p=0.027), and ulnar artery RI (p=0.008) could be the predictors for the development of DUs. Multivariate analysis further identified DUs at enrollment (odds ratio [OR]: 10.85; 95% confidence interval [CI]: 1.61-73.18; p=0.014) and anti-IFI-16 antibody (OR: 15.00; 95% CI: 1.13-199.18; p=0.040) as independent risk factors. Among patients without DUs at enrollment, new-onset ulcers occurred in 80% (4/5) and 4.5% (1/22) of those with and without anti-IFI-16 antibody, respectively (p=0.001).Conclusion:Anti-IFI-16 antibody is associated with vasculopathy in SSc and could be used as a novel biomarker for indicating the development of DUs.References:[1]McMahan ZH, Shah AA, Vaidya D, et al. Anti-interferon-inducible protein 16 antibodies associate with digital gangrene in patients with Scleroderma. Arthritis Rheumatol. 2016; 68(5): 1262-71.[2]McMahan ZH, Cottrell TR, Wigley FM, et al. Autoantigens targeted in scleroderma patients with vascular disease are enriched in endothelial lineage cells. Arthritis Rheumatol. 2016; 68(10): 2540–49.Figure 1.Multivariate logistic analysis for new or recurrent digital ulcers.Acknowledgements:The authors would like to thank Doctor Yi Cheng for performing Power Doppler ultrasound assessment.Disclosure of Interests:None declared

Author Correction: Up-regulation of Interferon-inducible protein 16 contributes to psoriasis by modulating chemokine production in keratinocytes

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abnormal Levels of Some Biomarkers of Immune Activation Despite Very Early Treatment of Human Immunodeficiency Virus

Background Despite early antiretroviral therapy (ART), ART-suppressed people with human immunodeficiency virus (HIV) (PWH) remain at higher risk for infections and infection-related cancers than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear. Methods ART-suppressed PWH and HIV-negative controls, all cytomegalovirus seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [early ART] vs later) and nadir CD4+ T-cell count among later initiators. Between-group differences in kynurenine-tryptophan (KT) ratio, interferon-inducible protein 10, soluble CD14 and CD163, soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor were assessed after confounder adjustment. Results Most participants (92%) were male, reflecting the demographics of early-ART initiators in San Francisco. Most biomarkers were higher among later-ART initiators. Participants in the early-ART group achieved near-normal soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor levels, but substantially higher KT ratio than those without HIV after confounder adjustment (P = .008). Soluble CD14, soluble CD163, and interferon-inducible protein 10 trended similarly. Conclusions While early-ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. Because this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this it may contribute to persistent risks of these complications in this setting.