Review: Cancer‐Induced Autoimmunity in the Rheumatic Diseases

Tantalizing connections between autoimmune rheumatic diseases and cancer have become increasingly evident over the past several decades. These connections are complex, with different relationships in frequency, timing, and types of cancers observed in different diseases or disease subgroups. Several recent advances from disparate fields have begun to illuminate the dynamic and bidirectional interactions occurring at the cancer–immune system interface which may be relevant to understanding the origins of autoimmunity (1). These interactions include the existence of potent anticancer immune responses that limit tumor growth, as well as multiple immune and inflammatory pathways that can contribute to tumor growth and robustness. The striking ability of immune checkpoint inhibitors to reveal powerful anticancer immune responses in patients with cancer highlights the fact that natural immune responses to cancers occur, and may regulate the emergence of cancer (2). Recent data from patients with systemic sclerosis (SSc, scleroderma) suggest that in some cases, autoimmunity may be initiated by autoantigen mutation in the patient's cancer (3, 4). Interestingly, there are patients with the same form of scleroderma and an identical autoimmune response who do not have a detectable cancer, raising the possibility that in these patients, the disease mechanism is the same except that the antitumor immune response has successfully eliminated the cancer. Similar striking associations with cancer are also apparent in other rheumatic phenotypes, particularly dermatomyositis (DM). The autoimmune rheumatic diseases therefore provide an exceptional opportunity to study cancer–immune system interactions and interrogate the mechanisms of the autoimmune rheumatic diseases, as well as the natural immune response to cancers in humans. This review highlights the relationships between cancer and rheumatic diseases, focusing on kinetics (how closely in time the cancer and rheumatic disease present) and immune response (the frequency of cancer in rheumatic disease patients with different autoantibody specificities). We will highlight similarities to various paraneoplastic, immune-mediated processes and will introduce important new tumor-immunoediting concepts. While space constraints require that this review focus on specific immune responses associated with cancer in SSc and DM, the principles outlined are likely also relevant to other autoimmune rheumatic syndromes. Patients with DM and patients with SSc have an increased risk of cancer compared to general population–based controls after adjustment for age and sex, with reported standardized incidence ratios or relative risks ranging from 3.0 to 7.7 for DM and 1.4 to 3.2 for SSc (5-22). Table 1 highlights cancer sites for which these patients are at elevated risk. While men (8, 14, 23), older patients developing myositis and SSc (5, 17, 18, 22, 24-27), and patients with rapid and severe onset of disease (26, 27), with poor response to therapy, or with diffuse cutaneous SSc may also have a higher risk of malignancy, these have not been consistently identified as risk factors for cancer. In both rheumatic diseases, there is a close temporal relationship between malignancy and autoimmunity onset. This is most striking in DM, in which the majority of patients with a malignancy have cancer prior to myositis diagnosis (19, 21, 28), with myositis often being diagnosed within 2 years (21). The risk of malignancy development after diagnosis of myositis is highest in the first year after myositis diagnosis, and then gradually decreases over time (19-21). In patients with SSc and breast cancer, a similar temporal relationship has been observed (29, 30). This temporal clustering, in conjunction with reports suggesting that cancer therapy may improve outcomes in myositis (31) or SSc (32, 33), suggests a possible mechanistic relationship between malignancy and rheumatic disease. Investigating this relationship is complex because of the significant heterogeneity in clinical phenotypes, age at rheumatic disease onset, tumor types, and cancer and rheumatic disease therapies used in these patients. However, the strong associations between unique autoantibodies and the temporal clustering of cancer diagnosis with rheumatic disease onset suggest that immunologic subsets may be a critical filter in understanding the cancer–autoimmunity relationship. Autoantibodies have important diagnostic and prognostic power across the spectrum of the autoimmune rheumatic diseases. Within a given phenotype, different autoantibodies may be associated with distinct clinical phenotypes. Myositis and SSc autoantibodies illustrate this well, and we have therefore focused on these below. Interestingly, within the spectrum of myositis (34), well-characterized myositis-specific autoantibodies are associated with distinct phenotypes. For example, antibodies against the aminoacyl transfer RNA synthetases (especially anti–Jo-1) are found in myositis patients with a common set of clinical features including interstitial lung disease, mechanic's hands, nonerosive arthritis, and fever (the “antisynthetase syndrome”). Mi-2 antibodies are found exclusively in DM patients; these patients frequently have more severe skin rashes and respond better to steroid therapy. While antibodies against melanoma differentiation–associated gene 5 (MDA-5) are also DM specific, patients with this specificity typically do not exhibit clinical myopathy and frequently have interstitial lung disease (35). Yet another distinct clinical component of the myositis spectrum is associated with antibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase—these are a feature in patients with an immune-mediated necrotizing myopathy (36, 37). While clinical phenotypes associated with known autoantibodies are widely recognized, myositis autoantibodies have not, until recently, been meaningfully associated with cancer. The usefulness of autoantibodies as predictors of cancer-associated myositis was examined by Chinoy et al (38) in a study of 282 patients with myositis–connective tissue disease overlap. The investigators showed that patients with myositis-specific and myositis-associated antibodies that can be assayed by routinely available clinical tests have a significantly lower risk of an associated cancer compared to autoantibody-negative DM patients. Recently emerging data have shown that while this may be the case for the “well-established/historic” myositis autoantibodies, 2 new specificities do indeed appear to be associated with cancer. These, and evidence of their cancer association, are discussed below. A newly recognized DM-specific autoantibody, found in 13–21% of adult DM patients, was recently reported by 2 groups (39, 40). In both studies, cohorts of patient sera were screened by immunoprecipitation using radiolabeled cell lysates, enabling detection of a 155-kd protein. Although the cohort sizes and the numbers of antibody-positive patients were small, in both studies these antibodies were frequently detected in patients with an associated malignancy. The target of this new antibody specificity was identified as transcription intermediary factor 1γ (TIF1γ) (41). This multifunctional protein is a member of the tripartite motif–containing protein family and has complex effects on various cellular pathways. For example, TIF1γ plays a critical role in tissue differentiation through interactions with Smad proteins (42). Thus, in embryonic stem cells, TIF1γ interacts with Smad2/3, allowing this complex to activate specific differentiation genes by promoting transcriptional elongation (43). TIF1γ is also required for proper development of mammary glands, where it inhibits Smad4 by ubiquitinylation (44). To evaluate the usefulness of TIF1γ antibodies for diagnosing cancer-associated DM, Trallero-Araguas et al (45) performed a systematic review and meta-analysis using data from 6 published studies; immunoprecipitation from lysates was used for antibody detection in all of these studies. The meta-analysis showed that anti-TIF1γ–positive DM patients have a 27-fold higher odds of developing cancer-associated myositis than their anti-TIF1γ–negative counterparts (45). In 1997, the presence of antibodies against a 140-kd protein (anti-MJ) in 18% of patients with juvenile DM was reported (46). The targeted autoantigen was subsequently found to be the nuclear matrix protein NXP-2 (47), a protein that localizes to the promyelocytic leukemia nuclear bodies and the nucleoplasm (38). There are 3 structurally separated, conserved domains (48) with important roles in various functions. For example, Mimura et al (38) showed that NXP-2 recruits and activates p53, inducing cellular senescence and thereby preventing cell proliferation. Initial studies of this specificity were performed on pediatric DM cohorts (49, 50), confirming a prevalence of ∼23–74%. They are notable for the lack of reported malignancy among the >200 young patients studied. More recent studies in adult myositis populations have demonstrated prevalences of anti–NXP-2 ranging from 1.6% to 30% of adult DM patients and 1.6% to 8% of adult polymyositis (PM) patients (51, 52). Of interest, Ichimura et al (52) noted that associated cancers were present in 3 of the 7 anti–NXP-2–positive DM patients in their cohort (43%), with all of the carcinomas being at an advanced stage. Intriguingly, 6 of the 7 anti–NXP-2–positive DM patients were male (86%), and all 3 of the cancers in the group were in male patients; the cancers were not restricted to male-specific cancer sites. Identification of specific antibodies in the 140–155-kd range following immunoprecipitation from lysates is challenging as there are multiple specificities in this size range (including TIF1γ, NXP-2, and MDA-5). We and our colleagues therefore recently developed sensitive, specific assays that unequivocally detect antibodies against NXP-2 and TIF1γ (53). Using these, antibodies against TIF1γ and NXP-2 were evaluated in 213 patients from 2 separate, well-defined DM cohorts (111 patients from the Department of Dermatology, Stanford University [Stanford, California] School of Medicine and 102 from the Myositis Center, Johns Hopkins University). Antibodies against TIF1γ and NXP-2 were detected in 82 of 213 DM patients (38%) and 37 of 213 DM patients (17%), respectively. The antibody groups were mostly non-overlapping, with only 2 patients having both specificities. Cancer-associated DM was detected in 29 of the DM patients (14%), with 24 of the 29 (83%) having antibodies against either TIF1γ or NXP-2. The overall frequency of cancer in TIF1γ/NXP-2–positive patients was 20.5%. In the remaining 96 patients with neither TIF1γ nor NXP-2 antibodies, there were only 5 cases of cancer (5%). An important relationship between age and cancer frequency in DM patients was noted across all antibody groups: among patients >60 years old, cancer was found in 55% of those with anti–NXP-2 antibodies, 31% of those with anti-TIF1γ antibodies, and 17% of patients without either of these antibodies. Additionally, antibodies against NXP-2 were specifically associated with cancer in male patients (7 of 9 [78%]). This observation is similar to findings in 3 patients reported by Ichimura et al (52). While the numbers in both of these studies are small, the results are intriguing and await confirmation. The above-described observations make several important points about the relationship between DM and cancer: 1) where cancers occur, they generally manifest around the time of DM diagnosis, irrespective of antibody response; 2) the prevalence of cancers within 3 years of myositis diagnosis is higher in anti-TIF1γ and NXP-2 autoantibody–positive groups; 3) among patients with TIF1γ or NXP-2 antibodies, however, a sizable proportion do not manifest cancer; 4) the frequency of cancers associated with DM increases at age >60 years, irrespective of serologic status; and 5) the association of NXP-2 antibodies and cancer in DM may be enhanced in males. Additional data are needed to confirm whether these findings are generalizable (particularly to different ethnic populations). The association of DM and cancer therefore does not appear to be binary but rather to be influenced strongly by several parameters, including autoantibody targets and age, although it is possible that a binary parameter remains to be defined. Of note, currently reported data regarding immune responses address overall autoantibody responses, but we do not yet understand the nuances of these specificities in terms of epitopes and magnitude, or the specificity of other immune effector pathways for these antigens. It is also possible that no individual covariate will be the key determinant of whether a cancer emerges clinically, but that the additive effects of multiple factors will be explicative. The close temporal clustering of DM and cancer, and the elevated frequency of cancer in patients with TIF1γ/NXP-2 antibodies irrespective of age, suggests that additional important parameters remain to be defined (see below). As in myositis, scleroderma-specific autoantibodies are associated with distinct clinical phenotypes and are useful for risk stratification and assessment of long-term prognosis (54-57). The 3 most common scleroderma-specific autoantibodies are anticentromere, anti–topoisomerase I (anti–topo I), and anti–RNA polymerase III (anti–RNAP III). 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