Protective Effect Against Cancer of Antibodies to the Large Subunits of Both RNA Polymerases I and III in Scleroderma

Abstract

Objective While compelling data suggest a cancer‐induced autoimmunity model in scleroderma patients with anti–RNA polymerase III large subunit (anti‐RPC155) antibodies, ~85% of these patients do not manifest cancer. This study was undertaken to determine whether additional autoantigens are targeted in anti‐RPC155–positive scleroderma patients without detectable cancer. Methods The study included 168 scleroderma patients with anti‐RPC155 antibodies (80 with a history of cancer and 88 with no cancer diagnosis after >5 years of follow‐up). Thirty‐five sera (17 from patients with cancer and 18 from patients without cancer) were randomly selected for autoantibody discovery using immunoprecipitation (IP). An ~194‐kd band was enriched in the subgroup without cancer; this was identified as RNA polymerase I large subunit (RPA194). Results RPA194 generated by in vitro transcription/translation was used for IPs performed on the entire cohort to test whether anti‐RPA194 was enriched among anti‐RPC155–positive patients without cancer. Anti‐RPA194 antibodies were significantly more common in the group without cancer (16 [18.2%] of 88) than in the group with cancer (3 [3.8%] of 80) (P = 0.003). Patients with both anti‐RPA194 and anti‐RPC155 were significantly less likely to have severe gastrointestinal disease than patients with anti‐RPC155 only (26.3% versus 51.0%; P = 0.043). Conclusion Anti‐RPA194 antibodies are enriched in anti‐RPC155–positive scleroderma patients without cancer. Since somatic mutations in the gene encoding RPC155 in cancer in scleroderma patients appears to play a role in immune response initiation against RPC155 in those patients, these data raise the possibility that the development of immune responses to both RPC155 and RPA194 may influence clinical cancer emergence. Further study is required to define whether different autoantibody combinations have utility as tools for cancer risk stratification in scleroderma.

Biphasic Temporal Relationship between Cancers and Systemic Sclerosis: A Clinical Series from Montpellier University Hospital and Review of the Literature

“…Yet, recently, Shah and colleagues described a particular subset of patients exhibiting RNA-PolIII antibodies, which target a specific subunit of RNApolIII (RPA194). These autoantibodies might have a "protective effect" against cancer as suggested by a higher prevalence among RNA-PolIII positive patients without cancer (16 positive sera in 88 SSc patients without cancer versus 3 in 80 patients with cancer) [31]. So, anti-RPA194 antibodies may stem from the development of cancer in a subgroup of patients [31], which is in line with the putative role of autoimmunity in the control of cancer spreading [32].…”

Association of systemic lupus erythematosus autoantibody diversity with breast cancer protection

“…The decreased risk of breast cancer in SLE patients has been intriguing in light of mechanistic data suggesting that cell-penetrating dsDNA antibodies may have anti-cancer effects in cells with DNA repair defects, such as BRCA2-deficient human cancer cells [ 11 ]. This, combined with recent data in scleroderma suggesting that unique immune responses and combinations of autoantibodies may associate with decreased cancer risk [ 3 , 6 ], raises the question as to whether dsDNA autoantibodies and/or the presence of multiple autoantibodies confers breast cancer protection in SLE.…”

“…For example, patients with dermatomyositis and antibodies against transcription intermediary factor 1-gamma (TIF1γ) or nuclear matrix protein 2 (NXP2) have an increased risk of cancer-associated myositis [ 2 ], and in systemic sclerosis (scleroderma), patients with anti-RNA polymerase III (POLR3) antibodies have a higher risk of cancer-associated scleroderma [ 3 – 5 ]. Intriguing new data demonstrate that scleroderma patients with anti-centromere antibodies have a lower risk of cancer than that expected in the general population and that scleroderma patients with autoantibodies against both POLR3 and the large subunit of RNA polymerase I (RPA194) have a lower frequency of cancer than those with anti-POLR3 alone [ 3 , 6 ]. These findings suggest that multiple, orthogonal immune responses targeting linked molecular machinery may confer cancer protection.…”

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

“…This suggests that either multiple mechanisms underlie the targeting of POLR3A by the immune system in SSc, and/or that cancer underlies many cases of SSc, but that in most cases the immune response is capable of controlling the cancer. In a recent study focused on SSc patients with autoantibodies against POLR3A in whom cancer does not emerge, we found that patients who also had autoantibodies against the large subunit of RNA polymerase I (RPA194) had a much lower incidence of cancer than those with antibodies against POLR3A alone ( 16 ). Because only 3 patients (3.8%) with anti-RPA194 antibodies developed cancer, it was not possible to distinguish whether this immune response identified a cancer-protective immune response versus a form of SSc unrelated to cancer.…”