Abstract IA11: Autoimmune rheumatic diseases and cancer: An example of natural cancer immunoediting?

A relationship between cancer and autoimmune rheumatic diseases has been observed for many decades, although the relevance of, and mechanisms underlying, this association have remained unclear. Investigating this relationship has been extremely challenging, due to heterogeneity of the rheumatic diseases across multiple dimensions, including kinetics of association of cancer and autoimmunity, the occurrence of cancer in only a subgroup of patients, variable exposure to drugs that are associated with increased incidence of malignancy, and the large number of tumor types associated with rheumatic disease. Several recent observations have provided important opportunities to understand the mechanisms underlying this relationship. (i) Increased cancer incidence across different autoimmune rheumatic diseases is associated with specific autoantibodies. For example, in scleroderma, patients with autoantibodies against RNA polymerase III or components of the minor spliceosome have increased cancer incidence both within cohort and compared to the general population. Similarly, in dermatomyositis, the majority of patients with concomitant cancer are found among patients with autoantibodies directed against either TIF1g or NXP2. (ii) In patients presenting with scleroderma and RNA polymerase 3 autoantibodies who have a concomitant cancer (within 3 years of scleroderma onset), there is evidence of somatic mutation and loss of heterozygosity at the POLR3A locus. There is evidence for T-cell immunity recognizing the specific mutations as well as the wild-type antigens. These findings are specific to patients with POLR3 antibodies and are not observed in patients with other autoantibody specificities. (iii) When comparing cancer incidence in different scleroderma subgroups defined by their autoantibody specificities to the SEER registry, there are striking differences in the SIRs in the different scleroderma subgroups. For example, patients with autoantibodies to POLR3 have an increased SIR for various cancers, while patients with autoantibodies to components of the centromere have strikingly decreased SIRs for cancer. (iv) A subgroup of scleroderma patients with autoantibodies recognizing POLR3 who do not manifest cancer have additional autoantibodies that recognize components of POLR1, suggesting that orthogonal immune responses might play important anticancer roles. Taken together, these data suggest a model in which autoantigen mutations in cancer induce immune responses to mutated and wild-type autoantigens. These immune responses are variably effective at preventing cancer emergence (in the majority of cases, either eliminating the cancers or maintaining them in equilibrium). Understanding the various mechanisms underlying those patients with autoimmune diseases where cancer does or does not emerge may provide important opportunities to understand natural cancer immunoediting, and how these mechanisms might be harnessed for treatment of cancer and avoidance of side effects in cancer immunotherapies. Citation Format: Antony Rosen. Autoimmune rheumatic diseases and cancer: An example of natural cancer immunoediting? [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA11.