Review: Cancer‐Induced Autoimmunity in the Rheumatic Diseases

Field: Medicine (Health Sciences)

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). Patients who are positive for antibodies targeting centromere proteins B/C tend to have limited cutaneous disease with features of CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), major ischemic digital loss, pulmonary hypertension, and overlap features with Sjögren's syndrome or primary biliary cirrhosis. In contrast, patients with anti–topo I antibodies have a higher risk of diffuse cutaneous disease and interstitial lung disease, and those with anti–RNAP III antibodies usually have aggressive, rapidly progressive diffuse cutaneous disease and a significantly higher risk of scleroderma renal crisis, myopathy, cardiac disease, and gastric antral vascular ectasia. Careful study of patients in these autoantibody subsets has demonstrated the usefulness of autoantibodies as predictors of cancer-associated scleroderma. Many investigations probing the relationship between cancer and scleroderma have excluded cancer cases diagnosed around the time of scleroderma onset, to avoid a potential detection bias. Consequently, patients with a close temporal relationship between cancer diagnosis and scleroderma onset have not been studied until recently. We investigated whether clinical characteristics among patients with scleroderma and cancer differed by autoantibody status (4). We demonstrated that in patients with RNAP III antibodies there was a close temporal relationship between malignancy diagnosis and the clinical onset of scleroderma, and patients exhibited a unique nucleolar RNAP III expression pattern in their cancerous tissues. These data suggested that expression of scleroderma antigens in cancers might be associated with scleroderma-specific autoantibody responses. The association between RNAP III antibodies and a close cancer–scleroderma interval has subsequently been confirmed by others (24, 30, 58). In an Italian scleroderma cohort, patients with RNAP III antibodies had a higher prevalence of cancer and were more likely to have cancer concurrent with scleroderma onset than patients with other autoantibodies (58). However, the study included only 16 anti–RNAP III–positive patients, 7 of whom had cancer. In a study of 451 Australian scleroderma patients, those with RNAP III antibodies had a 4.2-fold increased odds of having malignancy diagnosed within 5 years of scleroderma onset compared to patients without this specificity (24). The overall prevalence of cancer (∼13%) was similar between patients with and those without RNAP III antibodies (24). Another investigation in a cohort of 2,177 UK scleroderma patients demonstrated that the prevalence of malignancy was higher in patients with RNAP III antibodies (14.2%) than in patients with topo I antibodies (6.3%; P < 0.0001) or centromere antibodies (6.8%; P < 0.001) (30). Among patients with cancer diagnosed within 36 months of scleroderma onset, 55.3% were positive for RNAP III antibodies, whereas 13.6% were positive for topo I antibodies (P < 0.002) and 23.5% for centromere antibodies (P < 0.008) (30). These data suggest that patients with new-onset scleroderma and RNAP III antibody positivity may benefit from more aggressive evaluation for an underlying malignancy, given their heightened cancer risk. Interestingly, while a close cancer–scleroderma interval is most frequent among patients with RNAP III antibodies, there were patients with a short cancer–scleroderma interval and other autoantibody specificities in all studied cohorts. Since an anticancer immune response may be an important feature in some patients with scleroderma and RNAP III antibodies (see below), the co-occurrence (though infrequent) of cancer and scleroderma in these other serologic subgroups suggests that cancer may be an important initiator of the immune response in many scleroderma patients, but that an immune response against specific targets might exert more potent anticancer effects. Indeed, centromere proteins and topo I play important roles in cancer fitness and survival. These pathways are targets of potent anticancer therapeutic agents, including inhibitors of topoisomerase and the mitotic spindle, suggesting that immune responses to some pathways may have more deleterious effects on cancer growth and survival than others. In rheumatic diseases in which cancer incidence is low, it is possible that the other targets of the immune response may be effective therapeutic targets in cancers. It is also possible that distinct mechanisms (unrelated to neoplastic transformation), including infections and other cellular states, may underlie the immune targeting of centromere and topo I. It has been hypothesized that patients with cancer and rheumatic disease may develop cancer secondary to 1) target tissue damage from the autoimmune disease, or 2) cytotoxic therapies used to treat aggressive manifestations, or 3) as a consequence of a defective immune system that predisposes to the development of both cancer and autoimmunity (3, 59). However, data demonstrating unique nucleolar RNAP III expression in cancerous tissues from scleroderma patients with RNAP III antibodies (4), and the co-occurrence of cancer and scleroderma in this patient subset, raised the intriguing possibility that genetic alterations in the POLR3A locus in tumors may trigger autoimmunity. To address this, we studied tumors from 16 scleroderma patients: 8 with RNAP III antibodies and 8 with either centromere or topo I antibodies (3). The POLR3A locus had genetic alterations in 6 of 8 cancers from patients with RNAP III antibodies, but not in tumors from patients with other scleroderma antibodies. Interestingly, these genetic alterations took 2 forms: 1) Somatic mutations—3 patients had somatic mutations in POLR3A; in each, the mutation caused a change in a single amino acid (different in all 3 patients). The mutations were present at a diminished frequency in the cancers, suggesting that they arose quite late in cancer development, or that the mutations arose early and were negatively selected during cancer evolution (see loss of heterozygosity, below). It is noteworthy that mutations in POLR3A are very uncommon in cancer, with a frequency of 0.7% in the Cosmic database (P < 10−20), suggesting that these mutations help to the immune response to RNAP Indeed, 2 of the 3 patients with of RNAP III exhibited cell immune responses. The fact that mutations in specific as POLR3A are in cancers in general suggests that they are in the genes may autoimmunity to the immune system in the of the major complex A understanding of these relationships will require more data on frequency of mutations in additional 2) of of the 8 patients exhibited loss of at the POLR3A This was not a feature in cancers in scleroderma patients with other immune responses, including antibodies to topo I or centromere strongly that the RNAP immune response might be the evolution of the cancer, with (see below). of patients with scleroderma and RNAP III antibodies do not, however, manifest a cancer We therefore that potent antitumor immune responses successfully an underlying malignancy in most patients with scleroderma who manifest an autoantibody response against RNAP Although the immune response to RNAP III may be initiated against proteins in the patient's cancer, the presence of autoimmune to tissues do not the suggests that the immune response to the of the present in with this, we found that autoantibodies in the patients with RNAP III were with both and RNAP III (3). There is significant evidence demonstrating that a of a can a cell immune response to the and that the cell response the and antigens and antigens are present at the time of a cell response to the can be initiated We a similar mechanism with a cell a cell and and of a cell response against the While 1 patient in our study had the RNAP III against the RNAP III in scleroderma patients with and without cancer remains a for autoimmunity. of may in gene expression that in tissue (2). become these are not and not all cancer have The first immune response is against the form of the (4), and may to the effector against the in exclusively cancer the mutation effector against the in cancer without the mutation and also with the patient's tissues (particularly of found in autoimmunity has been the disease is that the immune-mediated can become the targets of the immune an of that the that the autoimmune There is significant evidence of of the immune response in various cancers. 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