Granzyme B Degraded Type IV Collagen Products in Serum Identify Melanoma Patients Responding to Immune Checkpoint Blockade

Christina Jensen*, Dovile Sinkeviciute, Daniel Hargbol Madsen, Patrik Onnerfjord, Morten Hansen, Henrik Schmidt, Morten Asser Karsdal, Inge Marie Svane, Nicholas Willumsen

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

34 Citationer (Scopus)
25 Downloads (Pure)

Abstract

Simple Summary

Novel biomarkers that can identify melanoma patients responding to immune checkpoint inhibitor therapy are urgently needed. As high T-cell infiltration and low fibrotic activity are associated with response, we aimed to examine the serum biomarker potential of granzyme B degraded type IV collagen (C4G) products in combination with the fibrosis biomarker PRO-C3. We found that high C4G combined with low PRO-C3 has the potential to identify patients responding to immune checkpoint inhibitor therapy suggesting that these biomarkers may provide a non-invasive tool for patient selection and therapeutic decision-making in the future.

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 (

OriginalsprogEngelsk
Artikelnummer2786
TidsskriftCancers
Vol/bind12
Udgave nummer10
Sider (fra-til)1-15
ISSN2072-6694
DOI
StatusUdgivet - 2020

Citationsformater