Granzyme B degraded type IV collagen products in serum identify melanoma patients responding to immune checkpoint blockade

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DOI

  • Christina Jensen, Nordic Bioscience AS, Københavns Universitet
  • ,
  • Dovile Sinkeviciute, Nordic Bioscience AS, Lund University
  • ,
  • Daniel Hargbøl Madsen, Københavns Universitet
  • ,
  • Patrik Önnerfjord, Lund University
  • ,
  • Morten Hansen, Københavns Universitet
  • ,
  • Henrik Schmidt
  • Morten Asser Karsdal, Nordic Bioscience AS
  • ,
  • Inge Marie Svane, Københavns Universitet
  • ,
  • Nicholas Willumsen, Nordic Bioscience AS

A T-cell permissive tumor microenvironment, characterized by the presence of activated T cells and low fibrotic activity is crucial for response to immune checkpoint inhibitors (ICIs). Granzyme B has been shown to promote T-cell migration through the basement membrane by the degradation of type IV collagen. In this study, we evaluated the biomarker potential of measuring granzyme B-mediated degradation of type IV collagen (C4G) in combination with a fibroblast activation biomarker (PRO-C3) non-invasively for identifying metastatic melanoma patients responding to the ICI ipilimumab. A monoclonal antibody was generated against C4G and used to develop a competitive electro-chemiluminescence immunoassay. C4G and PRO-C3 were measured in pretreatment serum from metastatic melanoma patients (n = 54). The C4G assay was found specific for a granzyme B-generated neo-epitope on type IV collagen. The objective response rate (ORR) was 2.6-fold higher (18% vs. 7%) in patients with high C4G levels (>25th percentile) vs. low levels (≤25th percentile). Likewise, high C4G levels at baseline were associated with longer overall survival (OS) (log-rank, p = 0.040, and hazard ratio (HR) = 0.48, 95%CI: 0.24–0.98, p = 0.045). Combining high C4G with low PRO-C3 correlated with improved OS with a median OS of 796 days vs. 273 days (p = 0.0003) and an HR of 0.30 (95%CI: 0.15–0.60, p = 0.0006). In conclusion, these results suggest that high granzyme B degraded type IV collagen (C4G) combined with low PRO-C3 quantified non-invasively has the potential to identify the responders to ICI therapy.

OriginalsprogEngelsk
Artikelnummer2786
TidsskriftCancers
Vol/bind12
Nummer10
Antal sider15
ISSN2072-6694
DOI
StatusUdgivet - okt. 2020

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