Abstract IA22: Autoimmune rheumatic diseases and cancer
Authors: Casciola-Rosen Livia , Shah Ami , Rosen Antony 
Published: February 2019

Some rheumatic disease autoantibodies are powerful markers of subgroups of patients who have distinct disease phenotypes and trajectories. Of particular interest are markers of several disease subgroups in whom cancer and rheumatic disease onset are clustered together in time. For example, a subgroup of scleroderma patients have coincident onset of cancer and scleroderma. This is observed in scleroderma patients with autoantibodies against RNA polymerase-3 (POLR3), and more recently with autoantibodies recognizing the minor spliceosome. In autoimmune myopathies, temporal clustering of diagnosis of cancer and myositis is associated with autoantibodies to NXP2 and components of the TIF1 complex. Interestingly, although the incidence of cancer is higher in patients with these autoantibodies, most patients with these autoantibodies do not manifest cancer, even with extended periods of follow-up. These observations provide an important opportunity to investigate the potential mechanisms which operate at the cancer-immune interface during development of rheumatic diseases. In cancers from anti-POLR3-positive scleroderma patients with a short scleroderma-cancer interval, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to POLR3 but not in eight patients without these antibodies. 3 antibody-positive patients had somatic mutations in POLR3A; 5 patients had loss of heterozygosity at the POLR3A locus. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations sparked cellular immunity and cross-reactive humoral immune responses. In a larger scleroderma cohort (&gt;2300 patients), the incidence of cancer in various autoantibody subgroups was compared to data from the Surveillance, Epidemiology and End Results (SEER) Program. An increase in cancer incidence in scleroderma patients with POLR3 autoantibodies was observed compared to the general population; strikingly, patients with anti-centromere autoantibodies had a lower cancer incidence than observed in the general population. The finding that distinct serologic subgroups have different cancer risks suggests that cancer immunity may be a common principle across the scleroderma spectrum, with cancer emergence influenced by the effectiveness of the different immune responses. For example, in scleroderma patients with anti-centromere antibodies, cancer emergence may be inhibited, while inhibition of cancer emergence may only be partial for anti-POLR3. Prior studies in small cohorts of breast cancer patients have demonstrated that anti-centromere antibodies may be present, and may associate with improved disease-free and overall survival. Additionally, recent data also suggest that anti-DNA antibodies can have direct anti-cancer effects in cells with DNA repair defects, possibly explaining the decreased risk of breast and other cancers observed among patients with SLE.Taken together, these data suggest that at least some patients with autoimmune rheumatic diseases such as scleroderma may represent natural cancer immunoediting in humans. In the simplest model, somatic mutations in autoantigens in different cancers initiate an immune response to the mutated autoantigen, which spreads to include the wild type version, and exerts both an anti-cancer effect as well as causes damage or dysfunction of normal tissues. Understanding the mechanisms underlying the range of efficacies of the anti-cancer effects in different patients and subgroups may provide important insights into how the anti-cancer immune response in autoimmune diseases might be more effectively harnessed therapeutically.

Citation Format: Livia Casciola-Rosen, Ami Shah, Antony Rosen. Autoimmune rheumatic diseases and cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA22.