Biomarkers of Cancer-Associated Myositis

Overview

The project is about dermatomyositis (DM), an autoimmune disease characterized by inflammation in the skeletal muscles and skin. Patients with DM have an increased risk of cancer, with a cancer incidence between 5.5% and 42%. Cancers in these patients are one of the leading causes of death. Some myositis-specific autoantibodies have been discovered and some of them are associated with cancer development. However, DM patients negative for all the known autoantibodies can also develop cancer. The Investigator hypothesized that antibodies against plasma membrane antigens and soluble immune checkpoints can be responsible for the association between cancers and autoimmunity. Therefore, the present study aimed to identify novel antigens and immunological pathways in patients with DM with cancer versus patients with DM without cancer, to identify those patients who need cancer screening. The Investigators focus on soluble immune checkpoint molecules and autoantibodies directed against plasma membrane antigens.

Several studies have reported an association between cancers and autoimmune diseases. Mechanisms underlying this association are largely unknown, but similarity between antigens expressed by cells in tissues targeted by autoimmune reactions and cancer cells is likely one of the drivers. Moreover, chronic inflammation can favor cancer onset. Among autoimmune diseases, dermatomyositis (DM) has the highest association with cancers. About 25% of patients with DM, over 40 years old, have cancer at the time of diagnosis or develop cancer later. Common cancers include lung, breast, colon, prostate, and ovarian cancers. DM is a systemic inflammatory disease affecting skeletal muscle, skin, and other organs (e.g., lung). Cancer risk in patients with DM is higher compared to age- and sex-matched populations, both before diagnosis and in the three years following diagnosis (standardized incidence ratio: 3.8 - 17.29). DM is characterized by autoantibodies. Autoantibodies against transcriptional intermediary factor TIF1-gamma, nuclear matrix protein (NXP2), and SUMO1 activating enzyme (SAE1) are detected more frequently in patients with paraneoplastic DM compared to patients without cancers and healthy controls. In contrast, autoantibodies against Jo-1 are detected less frequently. However, the identification of patients with increased cancer risk remains incomplete since DM patients negative for all known autoantibodies also have an increased risk. While TIF1-gamma, NXP2, and Jo-1 are intracellular antigens, plasma membrane antigens are more likely involved in cancer-associated DM due to their accessibility to antibodies. Immune checkpoint molecules have emerged as key regulators of the immune system, crucial for self-tolerance and immune activation. They mainly act as ligand-receptor pairs, but several undergo alternative splicing, generating soluble isoforms. The production of soluble forms of immune checkpoints in DM is scarcely known. Autoantibodies against extracellular antigens and soluble immune checkpoints may contribute to the association between cancers and autoimmunity. Identifying circulating markers deregulated in cancer-associated DM will enable the identification of patients at risk, facilitating timely screening and interventions. Patients with dermatomyositis (DM) have an increased risk of developing tumors, making early detection crucial due to their worse prognosis. The currently known autoantibodies, such as anti-TIF1-gamma, anti-NXP2, and anti-SAE1, fail to identify all DM patients with associated tumors. Additionally, about 35% of DM patients are negative in standard autoantibody screenings but still exhibit a higher tumor risk. So far, the identified autoantibodies in cancer-associated DM target intracellular antigens, which are unlikely to have a direct pathogenic role as they cannot bind their targets under physiological conditions. Soluble immune checkpoints are believed to mediate the relationship between DM and cancer, potentially serving as biomarkers. The study hypothesizes that autoantibodies against cell surface antigens, which are more likely to be pathogenic, may be present in tumor-associated DM. It also proposes that changes in soluble immune checkpoint levels might contribute to DM-associated tumor development and could help identify at-risk patients. This is a prospective and retrospective study. For the prospective part, serum samples will be collected at the time of enrollment, before the initiation of chemotherapy or immunotherapy. For the retrospective part, patients enrolled in the study must have an available serum sample stored at -80°C, and potentially a muscle biopsy, fixed in formalin and embedded in paraffin, taken during the diagnostic phase.