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

Abstract

BACKGROUND. The 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. METHODS. Using 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. RESULTS. We 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 antiCCAR1–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). CONCLUSION. As 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.