Abstract
BackgroundExcessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). In the pursuit of finding biomarkers that predict treatment response, we evaluated the association between serum biomarkers of collagen and vimentin turnover and outcomes in metastatic melanoma patients treated with the anti-CTLA-4 antibody ipilimumab (IPI).MethodsType III collagen formation (PRO-C3), MMP-degraded type I, type III and type IV collagens (C1M, C3M and C4M), and citrullinated and MMP-degraded vimentin (VICM) were measured with ELISAs in serum from metastatic melanoma patients before (n = 66) and 3 weeks after (n = 52) initiation of IPI treatment. Biomarker levels were associated with Disease Control Rate (DCR) and survival outcomes.ResultsWe found that baseline levels of PRO-C3 (p = 0.011), C1M (p = 0.003), C3M (p = 0.013) and C4M (p = 0.027) were significantly elevated in patients with progressive disease (PD). Univariate Cox regression analysis identified high PRO-C3 (p = 0.021) and C4M (p = 0.008) as predictors of poor overall survival (OS) and the biomarkers remained significant when evaluated with other covariates (PRO-C3 (p = 0.049) and C4M (p = 0.046)). Multivariate analysis identified VICM as a predictor of longer OS (p = 0.026). Similarly, a high C3M/PRO-C3 ratio predicted for increased OS (p = 0.034). Only C3M (p = 0.003) and VICM (p < 0.0001) increased 3 weeks after treatment.ConclusionsECM and tissue remodeling quantified in pre-treatment serum were associated with response and survival outcomes in metastatic melanoma patients treated with IPI. This highlights the importance of addressing the ECM and stromal component non-invasively in future ICI studies.
Highlights
Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI)
High pre-treatment Type III collagen formation (PRO-C3), Matrix metalloproteinase (MMP)-degraded type I collagen (C1M), MMP-degraded type III collagen (C3M) and MMPdegraded type IV collagen (C4M) levels are associated with progressive disease Serum concentrations of five different ECM biomarkers: PRO-C3, C1M, C3M, C4M and Citrullinated and MMP-degraded vimentin (VICM), were measured at baseline
High C3M/PRO-C3 ratio at baseline associates with increased overall survival we examined if the ratio of type III collagen degradation to formation (C3M/PRO-C3) at baseline could give additional information when looking on Disease Control Rate (DCR) and OS
Summary
Excessive extracellular matrix (ECM) remodeling and a reactive stroma can affect T-cell infiltration and T-cell activity in the tumor and hereby influence response to immune checkpoint inhibitors (ICI). Melanoma is one of the most aggressive human cancers with a highly reactive stroma [11] This results in increased cleavage of collagen proteins by matrix-remodeling enzymes (such as matrix metalloproteinases (MMPs)), and the products may act as chemokines, cytokines and immune regulating agents [12, 13]. These small protein fragments containing specific protease-generated neo-epitopes, or ‘protein fingerprints’, are released into the circulation where they can be used as serological biomarkers directly reflecting disease pathogenesis [14]
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