Autoantibodies and Cancer Association: the Case of Systemic Sclerosis and Dermatomyositis

Several rheumatic diseases have a perplexing association with cancer. Unraveling this mysterious connection is likely to provide deeper understanding regarding mechanisms governing the onset of both autoimmunity and cancer immunity, in addition to providing clinicians much needed guidance around whom and when to screen for occult malignancy. Systemic sclerosis (scleroderma) and dermatomyositis are two diseases in which the association with internal malignancy is well-described and can be considered as models from which to gain important insights that likely have broader applicability. The past 15 years have witnessed a striking acceleration in understanding how these two diseases are related to cancer emergence–an important crack in this inscrutable armor has been the discovery and characterization of disease-specific autoantigens that are closely tied with risk of cancer emergence. The best-described examples of this are antibodies against anti-RNA polymerase III (anti-POL3) and transcription intermediary factor 1-gamma (anti-TIF1γ). Patients with systemic sclerosis and cancer that are diagnosed within a short time interval of each other frequently have anti-POL3 antibodies. Antibodies against the minor spliceosome protein RNA-Binding Region Containing 3 (RNPC3) are also associated with increased cancer incidence in systemic sclerosis. Similarly, in the dermatomyositis spectrum, the majority of anti-TIF1γ-associated cancers are detected around the time of DM onset (most often within 1 year). Antibodies against Nuclear Matrix Protein 2 are also potentially associated with increased cancer emergence in dermatomyositis. The systemic sclerosis/anti-POL3 connection with close cancer onset led to the first experiments directly supporting the concept that rheumatic disease may in fact be a manifestation of cancer. It is now clear that studying these diseases through the lens of autoantibodies can reveal relationships and insights that would otherwise remain obscured. Extending these studies, new findings show that antibodies against RNA polymerase I large subunit are associated with protection against short interval cancers in anti-POL3-positive systemic sclerosis patients. These insights highlight the fact that autoantigen discovery related to cancer emergence remains an important priority; such new tools will enable the testing of specific hypotheses regarding mechanisms governing disease emergence and development of effective anti-tumor responses. Autoantibody phenotype will likely play an important role in the development of cancer screening guidelines that are critically needed by clinicians taking care of these patients. In this review, we will summarize the current state of knowledge regarding the different ways in which autoantibodies are connected with systemic sclerosis/dermatomyositis and malignancy and highlight potential paths forward.