Serological assessment of collagen fragments and tumor fibrosis may guide immune checkpoint inhibitor therapy

Abstract

Despite the overall clinical success of immune checkpoint inhibitors (ICIs) for treating patients with solid tumors, a large number of patients do not benefit from this approach. Consequently, there is a need for predictive biomarkers. The most prevalent biomarkers such as PD-L1 expression and tumor mutational burden (TMB) do not reliably predict response to ICIs across different solid tumor types suggesting that a broader view of regulating factors in the tumor microenvironment is needed. Emerging evidence indicates that one central common denominator of resistance to ICIs may be fibrotic activity characterized by extracellular matrix (ECM) and collagen production by cancer-associated fibroblasts (CAFs). A fibroblast-and collagen-rich stroma attenuates immunotherapy response by contributing to inhibition and exclusion of T cells. Here we review opportunities and limitations in the utilization of the most prevalent biomarkers for ICIs and elaborate on the unique opportunities with biomarkers originating from the activated fibroblasts producing an impermeable ECM. We propose that ECM and collagen biomarkers measured non-invasively may be a novel and practical approach to optimize treatment strategies and improve patient selection for ICI therapy.

Keywords: Biomarker; Collagen; Extracellular matrix; Fibroblasts; Immune checkpoint inhibitor; Immunotherapy; T cells; Tumor fibrosis.

Fig. 1

Response to immunotherapy is associated with balanced collagen formation and degradation in the tumor microenvironment. a A fibrotic tumor microenvironment characterized by high cancer-associated fibroblast (CAF) activity, transforming growth factor-beta (TGF-β) signaling, and extracellular matrix (ECM) and collagen formation is associated with T cell exclusion, immune suppression, and poor response to immune checkpoint inhibitors (ICIs). b T cell immunity and response to ICIs are associated with a balanced degree of ECM/collagen formation and degradation, and less CAF and TGF-β activity. c A fibrinolytic tumor microenvironment characterized by high matrix metalloproteinase (MMP) activity, and ECM and collagen degradation is associated with immune suppression and resistance to ICIs

Fig. 2

Fibroblast and tumor microenvironment-derived collagen fragments as blood-based biomarkers. a Consequent to increased fibroblast activity and protease-mediated collagen remodeling in the tumor microenvironment (TME), specific protein fragments are released into the circulation and can be used as non-invasive biomarkers assessed in a liquid biopsy (serum or plasma). Modified from Nissen et al., J Exp Clin Cancer Res, 2019. b The neo-epitope biomarker technology is based on monoclonal antibodies, which enables assessment of remodeling of specific collagens with diverse proteases. Measurement of the pro-peptide of type III collagen (PRO-C3) reflects fibrogenesis, while MMP degraded type III collagen (C3M) reflects fibrolysis. MMP degradation of the main basement membrane protein type IV collagen (C4M) reflects tumor invasiveness while granzyme B degraded type IV collagen (C4G) reflects T cell infiltration