Granzyme B degraded type IV collagen products in serum identify melanoma patients responding to immune checkpoint blockade
(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
- Jensen, Christina ; Sinkeviciute, Dovile LU ; Madsen, Daniel Hargbøl ; Önnerfjord, Patrik LU ; Hansen, Morten ; Schmidt, Henrik ; Karsdal, Morten Asser ; Svane, Inge Marie and Willumsen, Nicholas
- organization
- publishing date
- 2020
- 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
-
- scopus:85091714288
- pmid:32998446
- 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
- 2024-10-03 09:48:09
@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 (>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}}, }