Autoreactivity against Denatured Type III Collagen Is Significantly Decreased in Serum from Patients with Cancer Compared to Healthy Controls

Abstract

Autoantibodies have the potential as cancer biomarkers as they may associate with the outcome and immune-related adverse events (irAEs) following immunotherapy. Cancer and other fibroinflammatory diseases, such as rheumatoid arthritis (RA), are associated with excessive collagen turnover leading to collagen triple helix unfolding and denaturation with exposure of immunodominant epitopes. In this study, we aimed to investigate the role of autoreactivity against denatured collagen in cancer. A technically robust assay to quantify autoantibodies against denatured type III collagen products (anti-dCol3) was developed and then measured in pretreatment serum from 223 cancer patients and 33 age-matched controls. Moreover, the association between anti-dCol3 levels and type III collagen degradation (C3M) and formation (PRO-C3) was investigated. Anti-dCol3 levels were significantly lower in patients with bladder (p = 0.0007), breast (p = 0.0002), colorectal (p < 0.0001), head and neck (p = 0.0005), kidney (p = 0.005), liver (p = 0.030), lung (p = 0.0004), melanoma (p < 0.0001), ovarian (p < 0.0001), pancreatic (p < 0.0001), prostate (p < 0.0001), and stomach cancers (p < 0.0001) compared to controls. High anti-dCol3 levels were associated with type III collagen degradation (C3M, p = 0.0002) but not type III collagen formation (PRO-C3, p = 0.26). Cancer patients with different solid tumor types have downregulated levels of circulating autoantibodies against denatured type III collagen compared to controls, suggesting that autoreactivity against unhealthy type III collagen may be important for tumor control and eradication. This autoimmunity biomarker may have the potential for studying the close relationship between autoimmunity and cancer.