Immune responses to CCAR1 and other dermatomyositis autoantigens are associated with attenuated cancer emergence

• Published in: The Journal of clinical investigation 2022-01, Vol.132 (2), p.0_1-14
• Main Authors: Fiorentino, David F, Mecoli, Christopher A, Rosen, Matthew C, Chung, Lorinda S, Christopher-Stine, Lisa, Rosen, Antony, Casciola-Rosen, Livia
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Apoptosis Regulatory Proteins - immunology; Apoptotic proteins; Autoantibodies; Autoantibodies - immunology; Autoantigens; Autoimmunity; Biomedical research; Cancer; Cell Cycle Proteins - immunology; Cell division; Clinical Medicine; Complications and side effects; Dermatomyositis; Dermatomyositis - epidemiology; Dermatomyositis - immunology; Development and progression; Female; Health aspects; HeLa Cells; Humans; Immune response; Immune system; Immunology; Immunoregulation; Male; Medical screening; Mutation; Neoplasm Proteins - immunology; Neoplasms - epidemiology; Neoplasms - immunology; Proteomics; Retrospective Studies; Risk factors; RNA polymerase; Transcription Factors - immunology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI150201

BACKGROUNDThe temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-γ (TIF1-γ). Nevertheless, many patients with anti-TIF1-γ antibodies never develop cancer. We investigated whether additional autoantibodies are found in anti-TIF1-γ-positive patients without cancer.METHODSUsing a proteomic approach, we defined 10 previously undescribed autoantibody specificities in 5 index anti-TIF1-γ-positive DM patients without cancer. These were subsequently examined in discovery (n = 110) and validation (n = 142) cohorts of DM patients with anti-TIF1-γ autoantibodies.RESULTSWe identified 10 potentially novel autoantibodies in anti-TIF1-γ-positive DM patients, 6 with frequencies ranging from 3% to 32% in 2 independent DM cohorts. Autoantibodies recognizing cell division cycle and apoptosis regulator protein 1 (CCAR1) were the most frequent, and were significantly negatively associated with contemporaneous cancer (discovery cohort OR 0.27 [95% CI 0.7-1.00], P = 0.050; validation cohort OR 0.13 [95% CI 0.03-0.59], P = 0.008). When cancer did emerge, it occurred significantly later in anti-CCAR1-positive compared with anti-CCAR1-negative patients (median time from DM onset 4.3 vs. 0.85 years, respectively; P = 0.006). Cancers that emerged were more likely to be localized (89% of anti-CCAR1-positive cancers presenting at stage 0 or 1 compared with 42% of patients without anti-CCAR1 antibodies, P = 0.02). As the number of additional autoantibody specificities increased in anti-TIF1-γ-positive DM patients, the frequency of cancer decreased (P < 0.001).CONCLUSIONAs the diversity of immune responses in anti-TIF1-γ DM patients increases, the likelihood of cancer emerging decreases. Our findings have important relevance for cancer risk stratification in DM patients and for understanding natural immune regulation of cancer in humans.TRIAL REGISTRATIONNot applicable.FUNDING SOURCESThe NIH, the Donald B. and Dorothy L. Stabler Foundation, and the Huayi and Siuling Zhang Discovery Fund.