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.

Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in patients with dermatomyositis with anti-TIF1γ autoantibodies

“…Recently, autoantibodies against other targets, including the cell division cycle and apoptosis regulator 1 (CCAR1) protein, were also found to be associated with decreased cancer prevalence among anti-TIF1γ-positive patients with DM21; anti-CCAR autoantibodies were present in 36% of those without cancer and in 22% of those with cancer. When the two cohorts of anti-TIF1γ-positive patients used in the current study are combined, anti-Sp4 autoantibodies were present in 49.4% (39 of 79) of those without cancer and 7.1% (2 of 28) of those with cancer.…”

Xist ribonucleoproteins promote female sex-biased autoimmunity

“…All samples were collected from patients seen at the Stanford outpatient clinics under an IRB-approved protocol, and all patients provided informed consent to participate. The dermatomyositis cohort has been described previously 69 . All patients met probable or definite DM by 2017 ACR/EULAR IIM Classification Criteria 70 .…”

Coexisting autoantibodies against transcription factor Sp4 are associated with decreased cancer risk in dermatomyositis patients with anti-TIF1γ autoantibodies

“…Despite the strong link between anti-TIF1γ autoantibodies and cancer, a malignancy never emerges in approximately 40% of DM patients with this autoantibody 2 . Recently, autoantibodies against cell division cycle and apoptosis regulator 1 (CCAR1) protein were found to be associated with decreased cancer prevalence among anti-TIF1γ-positive DM patients; they were present in 36% of those without cancer and in 22% of those with cancer 25 . In the current study, we discovered novel autoantibodies against Sp4 protein that appear to have a markedly stronger association with the absence of cancer in anti-TIF1γ-positive DM patients.…”