Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma

Abstract

BackgroundImmune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) receptor induce a response in only a subgroup of patients with metastatic melanoma. Previous research suggests that transforming growth factor beta signaling and a collagen-rich peritumoral stroma (tumor fibrosis), may negatively interfere with the interaction between T cells and tumor cells and thereby contribute to resistance mechanisms by immune-exclusion, while increased tumor infiltration of M1-like macrophages enhances T cell activity. Hence, the current study aimed to assess the relationship between blood-based markers of collagen or vimentin turnover (reflecting M1 macrophage activity) and clinical outcome in patients with metastatic melanoma after PD-1 inhibition.MethodsPatients with metastatic melanoma who were treated with anti-PD-1 monotherapy between May 2016 and March 2019 were included in a prospective observational study. N-terminal pro-peptide of type III collagen (PRO-C3) cross-linked N-terminal pro-peptides of type III collagen (PC3X), matrix metalloprotease (MMP)-degraded type III (C3M) and type IV collagen (C4M), granzyme B-degraded type IV collagen and citrullinated and MMP-degraded vimentin (VICM) were measured with immunoassays in serum before (n=107), and 6 weeks after the first administration of immunotherapy (n=94). The association between biomarker levels and overall survival (OS) or progression-free survival (PFS) was assessed.ResultsMultivariate Cox regression analysis identified high baseline PRO-C3 (Q4) and PC3X (Q4) as independent variables of worse PFS (PRO-C3: HR=1.81, 95% CI=1.06 to 3.10, p=0.030 and PC3X: HR=1.86, 95% CI=1.09 to 3.18, p=0.023). High baseline PRO-C3 was also independently related to worse OS (HR=2.08, 95% CI=1.06 to 4.09, p=0.035), whereas a high C3M/PRO-C3 ratio was related to improved OS (HR=0.42, 95% CI=0.20 to 0.90, p=0.025). An increase in VICM (p<0.0001; in 56% of the patients) was observed after 6 weeks of treatment, and an increase in VICM was independently associated with improved OS (HR=0.28, 95% CI=0.10 to 0.77, p=0.014).ConclusionsBlood-based biomarkers reflecting excessive type III collagen turnover were associated with worse OS and PFS after PD-1 inhibition in metastatic melanoma. Moreover, an increase in VICM levels after 6 weeks of treatment was associated with improved OS. These findings suggest that type III collagen and vimentin turnover contribute to resistance/response mechanisms of PD-1 inhibitors and hold promise of assessing extracellular matrix-derived and stroma-derived components to predict immunotherapy response.

Collagen Fragments Produced in Cancer Mediate T Cell Suppression Through Leukocyte-Associated Immunoglobulin-Like Receptor 1

“…MMP generated collagen fragments are abundant in cancer and correlate with poor prognosis (20,21). Collagen fragments also seem to contribute to therapeutic resistance since high levels of C1M in the circulation associate with poor response to anti-CTLA-4 therapy (22), and increased collagen turnover is associated with poor survival after anti-PD-1 therapy (42). Furthermore, LAIR-1-collagen interaction has been implicated in mediating resistance to current anti-PD-1 immunotherapy (26).…”

Immune Modulatory Properties of Collagen in Cancer

“…As outlined in this review, collagen could be a novel target for improving the efficacy of immunotherapies such as checkpoint inhibitors (74,(175)(176)(177)(178)(179)(180), TIL-based therapy (181), and cancer vaccines (182). The hypothesis that collagen in the tumor microenvironment can affect the outcome of cancer immunotherapy is supported by studies that have identified the serum level of the N-terminal pro-peptide of collagen type III (PRO-C3) as a marker of poor prognosis following anti-CTLA-4 and anti-PD-1 checkpoint inhibitor therapy in metastatic melanoma patients (183,184). This serum marker is believed to reflect the presence of a highly collagen-dense tumor microenvironment (185).…”

The Extracellular Matrix-Derived Biomarkers for Diagnosis, Prognosis, and Personalized Therapy of Malignant Tumors

“…In patients with stage IV melanoma, collagen-derived biomolecules RO-C3, C1M, C3M, and C4M are biomarkers of poor response to the therapy with immune checkpoint inhibitor (ICI) ipilimumab (42). In patients with metastatic melanoma, blood-based biomarkers of type III collagen turnover are associated with worse overall survival and progress-free survival following PD-1 inhibition immunotherapy (43). In a clinical scenario, the ECM-turnover associated with the response of melanoma to immuno-therapy might be assessed in a "liquid biopsy" (44), and allows to stratify patients with metastatic melanoma according to their response to ICI therapy (45).…”

“…Aforementioned, many soluble ECM-derived molecules arising from within a solid tumor can be found in a peripheral blood, are detectable using routine laboratory methods such as immunoassays (42,43), and may therefore be used as a noninvasive "liquid biopsy" biomarkers. This makes them very attractive for use in clinics (47), the only limitation of their use being sensitivity and specificity of the immunoassay.…”