Tissue-derived peripheral biomarkers that reflect activity of T-cells, macrophages, and neutrophils in patients with solid tumors
Introduction
By identifying and quantifying specific extracellular protein fragments with neo-epitopes that are generated by proteolytic cleavage and post-translational modifications specific for T-cells, neutrophils and macrophages, respectively, it is possible to develop peripheral biomarkers that reflect the activity of these immune cells.
Tissue-derived peripheral biomarkers that reflect the activity of T-cells (C4G), macrophages (VICM) and neutrophils (nordicCPa9™) has biomarker potential in solid tumors and may serve as prognostic, predictive and pharmacodynamic biomarkers in clinical trials investigating cancer immunotherapy.
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Serological assessment of cancer associated myo-fibroblast (myCAF) activity by collagen pro-peptide biomarkers provides high prognostic power
Introduction
Myofibroblast Cancer Associated Fibroblasts (myCAFs) are the main tumor fibrosis drivers and hence different from inflammatory CAFs (iCAFs). CAFs produce type III, V, VI and XI collagen that are the essential components of tumor fibrosis. Pro-peptides of these collagens can be quantified both in serum with the nordicPRO-C3™, PRO-C5, nordicPRO-C6™ and PRO-C11 biomarkers where they are prognostic for poor overall survival in patients with various solid tumor types and may be applied in vitro.
In this study we investigated the association and difference between myCAFs and iCAFs and their collagen expression profile and related that to data available data on serological assessments of nordicPRO-C3™, PRO-C5, nordicPRO-C6™ and PRO-C11, and cultured CAFs.
Profiling collagen expression in fibroblast from PDAC and NSCLC reveals that type V collagen and type XI collagen are found in myCAF. Biomarkers of these collagens can be measured in serum from cancer patients and are prognostic for poor overall survival. Thus, these data suggest that cancer associated myo-fibroblast (myCAF) activity can be assessed non-invasively by specific collagen pro-peptide biomarkers.
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Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis partly due to excessive activity of cancer-associated fibroblasts (CAFs). CAFs drive the fibrosis that causes excessive type III collagen and extracellular matrix deposition that in turn reduces drug response resulting in poor survival. High levels of the type III collagen serum biomarker nordicPRO-C3™ correlates with poor survival in PDAC. While TGF-β is thought to be one of the main drivers of nordicPRO-C3™ and tumor fibrosis, cytokines such as Interleukin 1 (IL-1) play a key role in the pancreatic tumor microenvironment and may play a significant role in also tumor fibrosis. In this study, we first investigated the potential of IL-1 in activating fibroblasts to drive fibrosis and produce nordicPRO-C3™. Subsequently, we established a co-culture of pancreatic cancer cells and pancreatic CAFs to investigate the anti-fibrotic properties of nadunolimab, a fully humanized ADCC-enhanced monoclonal IgG1 antibody that targets IL1RAP and disrupts both IL-1α and IL-1β signaling.
Co-cultures of pancreatic tumor cells and CAFs induced formation, including collagen type III formation, and nadunolimab inhibited the collagen type III formation, suggesting anti-fibrotic properties. Activated fibroblasts had induced type III collagen formation (nordicPRO-C3™) suggesting that IL-1 is a driver of tumor fibrosis in PDAC. Nadunolimab, which is currently in clinical development for treatment of pancreatic cancer, has the potential to counteract the detrimental, fibrotic progression in tumors by targeting IL1RAP and blocking both IL-1α and IL-1β signaling. These findings suggest that nordicPRO-C3™ could potentially be used for prognostic/predictive enrichment and as a pharmacodynamic marker in future studies evaluating anti-IL-1 modalities in PDAC.
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Non-invasive biomarkers of ECM turnover are prognostic for combinations of checkpoint inhibition immunotherapy in solid tumors
Introduction
Immune checkpoint inhibitors (ICIs) are being investigated in many different combinations (Table 1) but only a fraction of patients respond. This highlights the need for prognostic biomarkers that can help identify patients most likely to respond. Tumor fibrosis and the high collagen/ECM turnover in the tumor microenvironment – processes are closely related to response to ICIs and survival outcomes.
Across a diverse cohort of patients with metastatic cancer treated with different checkpoint inhibition regimens, non-invasive biomarkers associated with tumor fibrosis and collagen/ECM turnover (nordicPRO-C3™, PRO-C19, PRO-C20, TGF-β, reC1M and C4M) could identify cancer patients with poor prognosis.
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Unraveling collagen signatures in cancer-associated fibroblasts: A biomarker-driven approach
Introduction
The tumor microenvironment (TME) plays a crucial role in driving tumor development. Among the constituents of the tumor stroma, cancer-associated fibroblasts (CAFs) are a pivotal component. CAFs are actively involved in tumor progression by modulating the architecture of the TME through increased deposition of various collagens resulting in tumor fibrosis. Several studies have shown that CAFs have heterogeneity within, and between, individual tissues. TGF-β is thought to be the main driver of tumor fibrosis, however, the field lacks a characterization of the specific collagen deposition of CAFs from different tissues.
In this study, we investigated the fibrotic activity of CAFs from various tissues by measuring the production of three specific collagen peptides in vitro by use of non-invasive clinically validated biomarkers.
These findings underscore the heterogeneity in collagen production among CAFs from different indications, providing valuable insights into the ECM dynamics within distinct TMEs. Collagen-based non-invasive biomarkers further demonstrate the capability to differentiate between the fibrotic activity of CAFs isolated from different tissues. These insights support the utility of this model as a useful tool for anti-fibrotic drug screening.
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Novel tissue turnover biomarkers are associated with prolonged QTc and pulmonary arterial hypertension in patients with systemic sclerosis
Introduction
Systemic sclerosis (SSc) is characterized by vasculopathy and fibrosis of the skin and internal organs. Cardiovascular involvement is a frequent and significant contributor to morbidity and mortality in SSc. They can develop clinically silent and be difficult to detect. Novel tissue turnover biomarkers hold the potential to detect the manifestations before clinical overt disease, identify risk patients and monitor the disease course as well as improve our understanding of the pathophysiology in SSc.
The objective of this study is to measure a panel of collagen biomarkers in SSc and explore associations to cardiac involvement detected by ECG and to PAH.
Patients with SSc and prolonged ECG presented an altered tissue turnover, by an increased level of nordicPRO-C3™ and nordicPRO-C6™. In addition, SSc patients with presence of PAH had increased levels of nordicPRO-C3™ and nordicPRO-C6™ as well. presented an altered tissue turnover in presence of PAH, and with a QTc>450 ms. Our study indicates that they could serve as biomarkers of these manifestations and warrant further studies in cardiac disease in SSc.
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TNF-α and TGF-β Synergistically Promote Fibrogenesis in a In Vitro Model of Fibro-inflammation
Introduction
Systemic sclerosis (SSc) is a skin disease characterized by chronic inflammation leading to fibrosis, a process called fibro-inflammation. TNF-α is an inflammatory cytokine driving chronic inflammation in SSc, while TGF-β activation is a hallmark of fibrotic pathology. Fibrogenesis (wound healing) is characterized by granulation tissue formation consisting of mainly type III collagen.
The aim of this study was to investigate if primary human dermal fibroblasts treated with TNF-α and TGF-β1 had increased fibrogenesis compared to fibroblasts treated only with TGF-β1.
Inflammatory TNF-α stimulation increases TGF-β driven fibrogenesis in dermal fibroblasts, by promoting their formation of type III collagen and fibronectin. Consequently, biomarkers of type III collagen formation and fibronectin formation may be markers of early fibrosis in fibro-inflammatory skin disease.
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Is Skin Disease a Local Manifestation of Systemic Tissue Turnover? Serological Collagen Biomarkers Provide Important Information on Skin Diseases Arising from Mutations in Collagen Genes
Introduction
Collagens are the main constituents of the skin. Genetic mutations in type VI, VII, and XVII collagen cause skin diseases, such as atopic dermatitis, epidermolysis bullosa, and bullous pemphigoid. These are all characterized as systemic diseases, with local manifestations. Novel collagen biomarkers hold the potential to detect skin manifestations, monitor the disease course, as well as improve our understanding of the pathophysiology.
The aim of this study was to develop blood-based biomarkers of type VI, VII, and XVII collagen, and investigate their diagnostic potential for skin pathologies, including systemic sclerosis.
These biomarkers reflect the downstream effect of different genetic mutations leading to skin disease and may be useful to determine skin involvement in rheumatic diseases, including systemic sclerosis and psoriatic arthritis.
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Hi-drad-uh-NIE-tis sup-yoo-ruh-TIE-vuh – also known as hidradenitis suppurutiva (HS) – is a pathologically complicated skin condition, where chronic skin inflammation leads to abscesses and scarring. It is a systemic disease with local manifestations, meaning that the chronic insult to the skin is systemic, but it is physically located where skin rubs against skin, such as the armpits, groins and under the breasts. It is well known that immune cells, such as neutrophils and mast cells are involved, but what do we know about tissue remodeling?
When the beautiful collagens of the skin become a part of disease pathogenesis
Patients with HS not only experience pain from the neutrophil-rich tunnels but also from excessive tissue remodeling that causes scarring of the skin. These patients have an imbalance in tissue formation and tissue repair, partly due to the excessive activity of immune cells, which release enzymes that degrade the skin.
One group of tissue-degrading enzymes are matrix metalloproteinases, abbreviated as MMPs. These are released by macrophages, the most numerous inflammatory cells found in HS patients. MMPs infiltrate and contribute to HS pathology, signaling that increased activity of MMPs degrades the proteins of the skin tissue, such as collagens. This process can be quantified by specific blood-based biomarker assays targeting this pathological process.
Pathological fragments in HS may be used to identify disease types
In HS, biomarkers of tissue remodeling such as type III collagen degraded by MMPs (C3M), are associated with disease severity (Hurley Staging).
Figure 1. Biomarkers of tissue remodeling associate with Hurley Stages
C3M is released upon MMP activation and measures dermal tissue remodeling. This raises the question – can we use C3M to identify subtypes of patients based on their disease activity, and potentially molecular endotypes to help select the right treatment for the patients?
To address this, the levels of C3M are different depending on how active the disease is when divided into the Sartorious Score (HSS).
Finding the patients with high C3M levels reflects high disease activity, and may indicate a different subtype of patients needing a different treatment type.
Figure 2. Type II collagen degradation biomarker C3M as a patient stratification tool
Serum biomarkers of proteolytic tissue destruction, formation and macrophage activity can discern patients with IBD according to infliximab treatment non-response or response
Introduction
Characterized by chronic inflammation, patients with Inflammatory Bowel Disease (IBD) experience detrimental remodeling of their intestinal extracellular matrix (ECM). Treatment with anti-inflammatory drugs can reduce inflammation, leading to remission and tissue healing. However, adequate monitoring of patients is critical to ensure and maintain treatment response.
As potential surrogate markers of ECM remodeling, we investigated blood-based biomarkers of type III and -VII collagen and posttranslational modifications of vimentin in patients with IBD. Our aim was to determine the value of the C3M, PRO-C7, and VICM biomarkers for identifying and monitoring response to infliximab (IFX).
Quantifying a combination of non-invasive biomarkers of ECM remodeling and macrophage activity provided AUCs of 0.684 to 0.797 identifying responders to IFX treatment. Each biomarker provided value at the three different visits (Visit 1, 2, and 3). Combining all three biomarkers measured at each visit resulted in an AUC of 0.797 identifying responders to IFX treatment.
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