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

Jensen, Christina ; Sinkeviciute, Dovile LU ; Madsen, Daniel Hargbøl ; Önnerfjord, Patrik LU orcid ; Hansen, Morten ; Schmidt, Henrik ; Karsdal, Morten Asser ; Svane, Inge Marie and Willumsen, Nicholas (2020) In Cancers 12(10).
Abstract

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... (More)

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.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Biomarker, Collagen, Extracellular matrix, Fibrosis, Immune checkpoint inhibitor, Immunotherapy, Ipilimumab, Melanoma, T-cell infiltration, Tumor microenvironment
in
Cancers
volume
12
issue
10
article number
2786
pages
15 pages
publisher
MDPI AG
external identifiers
  • pmid:32998446
  • scopus:85091714288
ISSN
2072-6694
DOI
10.3390/cancers12102786
language
English
LU publication?
yes
id
e855789b-d044-4ab5-b567-ab9a418d9ad3
date added to LUP
2020-10-23 13:21:25
date last changed
2024-04-03 14:39:13
@article{e855789b-d044-4ab5-b567-ab9a418d9ad3,
  abstract     = {{<p>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 (&gt;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.</p>}},
  author       = {{Jensen, Christina and Sinkeviciute, Dovile and Madsen, Daniel Hargbøl and Önnerfjord, Patrik and Hansen, Morten and Schmidt, Henrik and Karsdal, Morten Asser and Svane, Inge Marie and Willumsen, Nicholas}},
  issn         = {{2072-6694}},
  keywords     = {{Biomarker; Collagen; Extracellular matrix; Fibrosis; Immune checkpoint inhibitor; Immunotherapy; Ipilimumab; Melanoma; T-cell infiltration; Tumor microenvironment}},
  language     = {{eng}},
  number       = {{10}},
  publisher    = {{MDPI AG}},
  series       = {{Cancers}},
  title        = {{Granzyme B degraded type IV collagen products in serum identify melanoma patients responding to immune checkpoint blockade}},
  url          = {{http://dx.doi.org/10.3390/cancers12102786}},
  doi          = {{10.3390/cancers12102786}},
  volume       = {{12}},
  year         = {{2020}},
}