The potential relationship between cancer and autoimmunity is intriguing. Patients with certain autoimmune rheumatic diseases are known to have an increased risk of developing certain malignancies. For example, patients with systemic lupus erythematosus have a 4-5 fold increased risk of developing lymphoma compared with the general population, and the risk is even greater for patients with primary Sjögren’s syndrome. Conversely, treatment of cancer with IFNα chemotherapy is known to induce a lupus-like syndrome in 5-20% of patients. Some rheumatic diseases have also been observed to occur coincidentally with cancer.
In a paper published this week in Science, Joseph et al. raise the intriguing possibility that neoantigens created by somatic mutations occurring in tumors may generate an autoreactive immune response, laying the foundation for potential autoimmune disease development.
The researchers looked at patients with scleroderma, an autoimmune rheumatic disease associated with fibrosis of the skin and destruction of blood vessels affecting several organs. Scleroderma (also called systemic sclerosis) is characterized by the presence of autoantibodies to specific antigens such as RPC1 (RNA polymerase III subunit), TOP1 (topoisomerase I), or CENPB (centromere protein B). Of particular interest to the researchers, coincidental timing of cancer and scleroderma has been observed in patients with anti-RPC1 autoantibodies. Joseph et al. therefore asked whether cancer might induce scleroderma by generating a mutated form of RPC1 that would then be recognized as non-self by the immune system and constitute a starting point for the development of autoimmunity.
Analyzing the genome of normal and malignant tissue from scleroderma patients with anti-RPC1 antibodies and coincident cancer, the researchers found that the tumors from 6 out of 8 patients had mutations (either somatic mutations or loss of heterozygosity) in POLR3A, the gene encoding RPC1. By contrast, none of the tumors from 8 scleroderma patients with either anti-TOP1 or anti-CENPB antibodies and coincident cancer carried mutations in POLR3A. Of note, patients with anti-TOP1 or anti-CENPB antibodies developed cancer a median of 14 years after the onset of their scleroderma, whereas anti-RPC1 antibody-positive individuals developed cancer shortly before or after the onset of scleroderma.
Immunological analysis showed that the patients’ anti-RPC1 antibodies reacted with both the wild-type and mutated forms of RPC1. CD4+ T cells reactive with mutated RPC1 peptides were found in two out of the three patients investigated whose tumors contained somatic POLR3A mutations (the reactivity was patient, peptide, and HLA specific). It is possible to imagine a scenario where T cells are initially specifically activated by the mutated part of RPC1, with the humoral response later spreading to non-mutated areas of RPC1 and generating a pool of antibodies that do not discriminate between wild-type and mutated RPC1.
Since POLR3A mutations are rare in cancer in general (0.7%), the researchers suggest that the presence of these mutations and the temporal clustering of cancer and anti-RPC1 antibody-positive scleroderma is unlikely to be purely coincidental and unrelated. Rather, they speculate that the POLR3A mutations in malignant cells are the source of the anti-RPC1 autoimmune response leading, in the presence of additional factors, genetic or environmental, to sustained tissue injury, autoimmunity, and the development of scleroderma.
The concept of cancer immunosurveillance tells us that malignant cells arising from time to time in the organism are kept in check by the immune system, which mounts an attack and eradicates those cells before they can lead to cancer. The data presented by Joseph et al. gives support to the possibility that such a process, while limiting the incidence of cancer, may occasionally give rise to an autoimmune response. In susceptible individuals, such a response may be prolonged and amplified, leading to full-blown autoimmunity.
Infections have also long been considered a potential trigger for autoimmune diseases. Interestingly, both situations (cancer and infection as triggers of autoimmunity) are variants of the same scenario: that of an initially beneficial immune response that is going awry.
Reference
Association of the autoimmune disease scleroderma with an immunologic response to cancer. Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, Boin F, Fava A, Thoburn C, Kinde I, Jiao Y, Papadopoulos N, Kinzler KW, Vogelstein B, Rosen A. Science. 2014 Jan 10;343(6167):152-7. doi: 10.1126/science.1246886
PMID: 24310608
Joseph CG, Darrah E, Shah AA, Skora AD, Casciola-Rosen LA, Wigley FM, Boin F, Fava A, Thoburn C, Kinde I, Jiao Y, Papadopoulos N, Kinzler KW, Vogelstein B, & Rosen A (2014). Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science (New York, N.Y.), 343 (6167), 152-7 PMID: 24310608
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