Immune responses to CCAR1 and other dermatomyositis autoantigens are associated with attenuated cancer emergence
David F. Fiorentino, … , Antony Rosen, Livia Casciola-Rosen
David F. Fiorentino, … , Antony Rosen, Livia Casciola-Rosen
Published January 18, 2022
Citation Information: J Clin Invest. 2022;132(2):e150201. https://doi.org/10.1172/JCI150201.
View: Text | PDF
Clinical Research and Public Health Autoimmunity Immunology

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 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).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.TRIAL REGISTRATION Not applicable.FUNDING SOURCES The NIH, the Donald B. and Dorothy L. Stabler Foundation, and the Huayi and Siuling Zhang Discovery Fund.

Authors

David F. Fiorentino, Christopher A. Mecoli, Matthew C. Rosen, Lorinda S. Chung, Lisa Christopher-Stine, Antony Rosen, Livia Casciola-Rosen

×

Figure 4

Protection against cancer is associated with combinatorial expression of autoantibodies.

Options: View larger image (or click on image) Download as PowerPoint
Protection against cancer is associated with combinatorial expression of...
(A and B) Number, identity, and frequency of unique autoantibody combinations in patients with (A) or without (B) cancer within 3 years of DM onset. The vertical histogram above the matrix shows the frequency of specific autoantibodies in the cohort of anti–TIF1-γ–positive patients, in order of decreasing magnitude. The y axis of those plots denotes number of patients. In the matrix itself, each row represents 1 autoantibody combination. Gray circles denote absence of a specific antibody, black circles denote presence, and when multiple specificities are present in a combination, they are connected by black lines. The frequency of each combination is shown in the horizontal bar plots; the x axis denotes the number of patients. (C) Mean number of autoantibody specificities in anti–TIF1-γ–positive DM patients in whom cancer does or does not emerge. Data at 1 year, 3 years, 5 years, and ever after DM diagnosis are shown (mean ± SEM, obtained by a bootstrapping procedure [n = 10,000 samples]). *P < 0.05; ***P < 0.001; ****P < 0.0001 by 2-tailed, independent 2-sample t test. (D) Proportion of DM patients in whom cancer does (“cancer”) or does not (“no cancer”) emerge within 3 years of DM diagnosis that have anti–TIF1-γ antibodies only (0) or anti–TIF1-γ plus additional specificities (1–5). Histograms of antibody count in excess of anti–TIF1-γ were computed and are shown. The cumulative distribution of antibody count in excess of anti–TIF1-γ was also computed for cancer versus no-cancer groups, and superimposed on the histograms (thin traces at top).