- Review
- Open Access
Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy
- Meleeneh Kazarian1 and
- Ite A Laird-Offringa1Email author
https://doi.org/10.1186/1476-4598-10-33
© Kazarian and Laird-Offringa; licensee BioMed Central Ltd. 2011
- Received: 13 July 2010
- Accepted: 30 March 2011
- Published: 30 March 2011
Abstract
Small-cell lung cancer (SCLC) is the most aggressive lung cancer subtype and lacks effective early detection methods and therapies. A number of rare paraneoplastic neurologic autoimmune diseases are strongly associated with SCLC. Most patients with such paraneoplastic syndromes harbor high titers of antibodies against neuronal proteins that are abnormally expressed in SCLC tumors. These autoantibodies may cross-react with the nervous system, possibly contributing to autoimmune disease development. Importantly, similar antibodies are present in many SCLC patients without autoimmune disease, albeit at lower titers. The timing of autoantibody development relative to cancer and the nature of the immune trigger remain to be elucidated. Here we review what is currently known about SCLC-associated autoantibodies, and describe a recently developed mouse model system of SCLC that appears to lend itself well to the study of the SCLC-associated immune response. We also discuss potential clinical applications for these autoantibodies, such as SCLC diagnosis, early detection, and therapy.
Keywords
- Paraneoplastic Neurologic Syndrome
- Epitope Spreading
- SCLC Patient
- Mouse Model System
- SCLC Cell Line
Introduction
Lung cancer is the leading cause of cancer-related death in the world, claiming the lives of 1.3 million individuals worldwide in 2007 [1]. In the United States, lung cancer killed over 150,000 Americans in 2009 [2, 3] and caused more deaths than breast, prostate, pancreatic, and colon cancer combined. Small-cell lung cancer (SCLC), a highly malignant tumor thought to originate from primitive neuroendocrine cells in the lung [4], accounts for up to 15% of all newly diagnosed lung cancers [5]. Cigarette smoking is the major cause of SCLC, where both the smoking intensity (cigarettes/day) and the number of years of smoking increase the risk of SCLC development [6]. Recently, it was shown that repetitive nicotine exposure induces many malignant features in SCLC cells, including increased adhesion, enhanced migration, and resistance to chemotherapy [7]. Initially, SCLC patients respond well to chemotherapy. However, relapses are inevitable as patients become resistant to cytotoxic treatment [8]. Despite treatment, the relative 5-year survival is only 6.4% [3], making SCLC the most aggressive lung cancer subtype.
There are as yet no effective early detection tools for SCLC. It is most often diagnosed due to symptoms associated with disseminated disease, such as bulky intrathoracic malignancy or distant metastases. Cough, shortness of breath, and chest pain are the most common local symptoms, and distant signs of the disease include weight loss and weakness. After presentation of symptoms, histological analysis of bronchoscopic biopsy samples and cytological study of fine-needle aspiration (FNA), transbronchoscopic needle aspiration (TBNA), or endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) samples are common approaches to confirm SCLC diagnosis [9–12]. The cancer is defined as a malignant epithelial tumor consisting of small cells with altered cytoplasm, ill-defined cell borders, granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells can be round, oval, or spindle-shaped [13]. It can be difficult to pathologically distinguish SCLC from other lung malignancies, including neuroblastoma, embryonal rhabdomyosarcoma, desmoplastic small round cell tumor, primitive peripheral neuroectodermal tumors [14], poorly differentiated squamous cell carcinomas, and large cell carcinomas [10]. Epithelial markers, such as cytokeratins, and neuroendocrine markers can be employed to differentiate SCLC tumors from the aforementioned lung malignancies. Sampling error is the most commonly reported cause of false negatives in lung FNA cytology [10, 15]. SCLCs are centrally located, and accessing them by FNA is more difficult in comparison to peripherally located adenocarcinomas and metastatic neoplasms [10]. In addition, the small size of the cells increases the chances of crushing the sample by biopsy forceps or distorting the sample during needle aspiration [16]. Given that accurately diagnosing SCLC can be difficult, the development of additional methods, such as detection of molecular markers associated with this disease, may increase the efficacy of diagnosis. Molecules that might be suitable for this purpose are SCLC-associated autoantibodies. Examples of such antibodies are those found in paraneoplastic neurologic syndromes associated with SCLC.
Paraneoplastic neurologic syndromes (PNS) are defined as cancer-associated neurological diseases that damage neuronal tissues in a site remote from the tumor (unrelated to metastasis) [17]. PNS patients typically harbor antibodies directed against neuronal antigens that are abnormally expressed in the tumor. Thus, the tumor and the immune system are both implicated in the development of PNS [18–20]. A number of PNS are strongly associated with SCLC. They are severely debilitating and often are the cause of death in SCLC patients who are affected by them. While these autoimmune diseases are quite rare, affecting a small percentage of SCLC patients [18], the characteristic antibodies can actually be found in a substantial fraction of SCLC patients without neurological symptoms, albeit at low titers. This suggests that these antibodies may have utility for early detection and diagnosis of SCLC. In order to be of use for early detection, the timing of the antibody response in relation to that of SCLC development and progression has to be clearly established. In the case of SCLC-associated PNS, the diagnosis of the neurological disease often antedates that of the tumor [18, 21], suggesting that the body's immune system can detect the presence of SCLC before the cancer becomes symptomatic. If such antibodies were to generally arise prior to tumor metastasis in SCLC patients, they could potentially provide an avenue for early detection.
The mechanism by which autoimmunity develops in SCLC remains to be elucidated. For example, it is unclear whether the antigens that prompt an immune response are in any way different from those in normal tissue. If these antigens exhibited cancer-specific changes responsible for triggering an antibody response, they might not only be useful for the development of tools for (early) detection, but also for imaging and treatment. Thus, elucidating the basis of immune reactivity in SCLC is of great importance. The study of SCLC-associated PNS offers a potential window into the relationship between SCLC and the immune response.
SCLC-related autoantigens and autoantibodies
Induction of immuno-responsiveness in SCLC
The mechanisms that trigger and maintain an autoimmune response in cancer patients are poorly understood. An autoimmune response is a specific immune response to a self-antigen, and autoimmune diseases occur because the immune system is incapable of discriminating between self-antigens that are normally expressed and those that are abnormally or ectopically expressed. Some SCLC-associated autoantigens, such as the Hu and SOX1 proteins, are intracellular antigens. The following sections will discuss various hypotheses concerning the induction mechanism of immuno-responsiveness against self-antigens, including abnormal expression of proteins, tolerance disruption, cross-reaction with membrane antigens, and protein modifications that generate "neo-antigens".
Abnormal expression of self-antigens and the immune privilege of neurons
SCLC-associated autoimmunity may arise as a consequence of abnormal self-antigen expression by tumor cells. Ectopic expression of a self-antigen alone is not sufficient to initiate an immune response; the immune system must somehow be activated. It is understandable that a mutation or modification of a self-antigen could render it foreign; however, if this is not the case, another explanation must exist. Many tumor-associated antigens are not unique to tumor cells. Most SCLC-associated antigens are normally expressed in the nervous system and gonads, and the tumor antigen and natural antigen appear to be identical. In these cases, the antigen may present in a way that the immune response is unaccustomed to, either at an increased level of expression or altered localization, which could be detected by the immune system, initiating an immune response.
An important question to address is why only a fraction of patients harbor an immune response when many of the antigenic proteins are aberrantly expressed in almost all SCLC tumors? For example, 16-25% of SCLC patients have an anti-Hu response without neurological disease [26, 31, 49, 52, 88] even though all SCLC tumors express the antigen [89]. This suggests that those cells expressing the antigen may be immune privileged, allowing evasion of an immune response. A recent study found that HuD-specific CD8+ T cells were normally present in C57BL/6 mice, but these T cells did not expand upon immunization with an adenovirus expressing HuD. The T cells were stimulated only when the splenocytes from these immunized mice were stimulated in vitro. These cells were able to recognize the antigen in vivo, but were prevented from becoming effector cytotoxic T cells, suggesting that the mice were strongly tolerant to the self-antigen HuD protein. Furthermore, after HuD immunizations or HuD CD8+ T cells through adoptive transfer, these mice did not develop evidence of neurologic dysfunction or abnormality. Further evidence for tolerance to HuD comes from experiments with HuD null mice, where HuD is not a self-antigen. These mice generated functional HuD-specific T cells, and these cells were directly activated without the need for in vitro stimulation with a peptide [90]. Taken together, these results demonstrated a robust tolerance to HuD in vivo.
Most SCLC-associated autoantigens are normally expressed in a neuron-specific manner. Neurons do not normally express major-histocompatibility complex (MHC) class I molecules [91], thus they may be immune privileged cells that can evade immune surveillance. It was observed that some SCLC tumors from patients with PEM/SN did express MHC class I molecules, whereas amongst 20 tumors from patients with detectable anti-Hu autoantibodies and no PEM/SN, only one showed modest expression of MHC class I molecules [41]; tumors from most seronegative patients did not express MHC proteins. Together, these studies indicate that tolerance to neuronal antigens may be present, and that its disruption might contribute to SCLC-associated autoimmunity.
Modifications of self-antigens to generate "neo-antigens"
An alternative hypothesis for the autoimmune response in SCLC is that the antigenic protein might be mutated or modified in a way that renders it foreign to the immune system. It is possible that the tumors express similar, but not identical forms of the antigen. For example, mutations or alternative splicing may generate different forms of the protein. In a recent study, the HuD sequence of four SCLC tumors and five SCLC cell lines was determined [92]. A missense mutation was identified in two tumors, but it was unclear whether the mutations were single nucleotide polymorphisms (SNPs) or somatic mutations. None of the cell lines showed HuD mutations, although several had SNPs. A previous study of 18 SCLC cell lines, including one from the tumor of a patient with PEM/SN, also failed to identify mutations or rearrangements in HuD [93]; the same was true in an analysis of paraneoplastic SCLC tissue [94]. However, these studies did not examine the related genes HuB and HuC, which are often misexpressed in SCLC and to which anti-Hu autoantibodies are cross-reactive. No mutations were found in the cerebellar degeneration-related (cdr2) gene, which encodes a neuron-specific protein in breast and ovarian tumors associated with PCD [95]. Overall, there is little evidence for the involvement of mutations in SCLC-associated autoimmunity, however further studies are needed to eliminate this as a potential factor.
Another possible explanation for immunogenicity of SCLC-associated autoantigens is that proteins triggering the autoimmune response might carry abnormal post-translational modifications. Over 140 unique amino acids and amino acid derivatives are reported to exist in proteins as a result of post-translational modification [96]. Such modifications include glycosylation, phosphorylation, methylation, acetylation, deamidation, and isomerization (reviewed in [97, 98]). These modifications can be enzyme-mediated or spontaneous. Abnormal post-translational modifications can lead to the generation of "neo-self" antigens which the immune system recognizes as foreign and to which it mounts an immune attack. For example, experimental autoimmune encephalomyelitis (EAE) is only induced in a murine model for human multiple sclerosis when mice are immunized with an acetylated N-terminal peptide of myelin basic protein (MBP-Ac1-11); no T cells are stimulated and no EAE is elicited upon immunization with the non-acetylated form of the peptide [99]. A number of autoimmune diseases, including multiple sclerosis, experimental allergic encephalomyelitis, systemic lupus erythematosus, and rheumatoid arthritis, are associated with post-translational modifications (reviewed in [96, 98, 100]). Recently, changes in IgG Fc N-glycosylation were observed in LEMS and myasthenia gravis (MG) patients [101]. Antibodies elicited as a result of modified self proteins are often able to bind both the modified and unmodified form of the protein, possibly by epitope spreading; however, the T cell response is usually specific for the modified form, retaining tolerance for the normal protein [97].
To our knowledge, the association between post-translational modifications of SCLC-associated autoantigens and SCLC-related autoimmunity has not been examined. It is possible that post-translational modification of neuronal proteins in SCLC tumors initiates an immune response which may cross-react with native proteins in the healthy nervous system and, in extreme cases, leads to paraneoplastic disease. Therefore, the role of post-translational modification as a trigger of SCLC-associated autoimmunity should be thoroughly investigated.
Pathogenicity of SCLC-associated autoimmune responses
Understanding the pathogenesis of SCLC-associated PNS is important to elucidate the mechanism by which the immune response arises as well as to clarify the potential limitations of harnessing the immune system to fight cancer. If mutated or aberrantly modified proteins originating from the cancer trigger the SCLC-associated immune responses then one might expect the response to be tumor-specific. How would reactivity spread to the native protein and lead to destruction of healthy tissue? One mechanism that has been proposed is epitope spreading [97, 102]. Epitope spreading is the gradual expansion of the spectrum of specificities recognized in B and/or T cell-mediated immune responses. Evidence for epitope spreading has been demonstrated by immunization experiments with a single peptide derived from an autoantigenic protein, giving rise to a T cell response or autoantibody production directed against epitopes that did not overlap with the immunizing peptide [102]. Analysis of B and T cell reactivity in autoimmune diseases does, however, suggest that the T cell response is frequently specific for the modified antigen, while the B cell response is more cross-reactive [97]. This may be related to the mechanism by which antigens are displayed by MHC molecules and recognized by the T cell receptors [97]. In SCLC-associated autoimmunity, multiple epitopes are often recognized within a single antigen [91, 103], also supporting a role of epitope spreading in the pathogenicity of SCLC-associated paraneoplastic syndromes.
The tissue naturally expressing SCLC-associated autoantigens will affect the pathogenesis of PNS. In the case of SCLC-related autoimmunity, most of the autoantigens are neuronal; thus, certain parts of the nervous system would be targeted and affected. In addition, the cellular localization of the antigen in its natural context will also play a role. Synaptic proteins, for example, are more likely to be expressed on the cell surface [104], and a pathogenic role of autoantibodies against these antigens is therefore more likely than of antineuronal antibodies directed against intracellular proteins. Cell surface antigens can be directly recognized by antibodies and CD8+ T cells, which would result in a directed immune attack and subsequent apoptotic cell death of the offending cell. Apoptotic cells can present altered cleavage products and post-translationally modified self-proteins on surface blebs, further promoting autoimmunity [97].
Antibody binding may also affect the function of the target protein. In SCLC-associated LEMS, voltage-gated calcium channels (VGCCs) are found both in the tumor and the presynaptic cholinergic-synapse and cerebellar Purkinje cells of the nervous system [66]. VGCCs are transmembrane proteins, and antibodies reacting with them in the tumor and the nervous system bind and disrupt the normal structure of the extracellular protein, possibly contributing to the development of LEMS. Anti-Nova antibodies (Table 1) have been shown to play an inhibitory role on Nova-1 binding to its RNA target [105], suggesting that the antibodies may disturb the function of the protein. Whether this biological effect contributes to the formation of paraneoplastic opsoclonus-myoclonus ataxia (POMA) is unknown.
It has been proposed that antibodies or cytotoxic CD8+ T cells can cross-react with antigens in the nervous system by penetrating the blood-brain barrier--a physical barrier separating the central nervous system from systemic circulation and restricting the passage of solutes into cerebrospinal fluid. These antibodies and T cells can then bind to the antigen expressed on the neurons and impair neuronal activity, triggering apoptosis [22]. For example, it has been hypothesized that anti-recoverin antibodies present in peripheral blood can penetrate the blood-retina barrier and become internalized into photoreceptor cells expressing recoverin, which could block recoverin function and lead to photoreceptor cell death [106–108]. Some onconeural antigens, such as Hu proteins, however, are normally expressed in the peripheral nervous system neurons where the blood-brain barrier does not exist [109]. Thus, an alternate model is likely in those cases.
While there is ample evidence for a role of antibodies in the pathogenesis of PNS, there are also examples of high titer antibodies with no overt neurological effect. For example, when mice were immunized with a HuD DNA or HuD protein vaccine, no neurological disease was observed even though an antitumor response that inhibited the growth of an implanted neuroblastoma was observed. Furthermore, passive transfer of IgG from anti-Hu patients to animals did not induce an autoimmune response [110, 111]. This suggests that a correlation exists between antitumor immunity and the presence of the antibodies, but that the antibodies are not causing the autoimmune disease. Thus, the pathogenicity of SCLC-related autoantibodies may be dependent on the antigen and its effect on its target cell. Cellular immunity has been shown to play a role during the course of SCLC-associated PNS. Several groups have reported a T cell response in anti-Hu positive patients, and a HuD-specific cytotoxic T cell response has been implicated in the development of PEM/SN [112–115]. A subpopulation of nontoxic T cells was also identified in PEM/SN patients, indicating that both classical cytotoxic T cells and noncytotoxic T cells may play roles in pathogenesis [114]. In seeming contrast to these observations, one group showed no evidence of HuD-specific T cells in the cerebrospinal fluid of SCLC-associated PEM/SN patients [116, 117]. However, the authors noted that the assay used may not have been sufficiently sensitive. Thus, the role of antigen-specific T cells in the pathogenesis of SCLC-associated autoimmunity is still under debate. It has been shown that major-histocompatibility complex (MHC) class I and MHC class II antigen-presenting molecules in neurons can be recognized by T cells which can kill neurons [118]. Intracellular proteins can be presented to T cells on the surface of MHC class I molecules. However, neurons do not normally express MHC class I molecules [91], indicating that these cells may be immune privileged, allowing evasion of T cell recognition.
Recently, attention has turned to the role of CD4+ CD25+ regulatory T cells (Treg), which are suppressor cells that maintain immune tolerance. Treg populations generally increase in and around cancer tissues, which potentially causes the down regulation of both effector T cell function and antitumor immunity, thereby contributing to cancer growth [119, 120]. However, LEMS and PEM/SN patients exhibited a down regulation of these T cells in comparison to SCLC patients without LEMS or PEM/SN [121], suggesting Treg dysfunction may play a role in the PNS development.
In summary, many questions remain about the pathogenicity of the SCLC-associated immune response, and the possibility that distinct mechanisms play a role in different paraneoplastic syndromes further increases the complexity of this disease state. Various hypotheses about the ectopic expression of autoantigens, the molecular state of antigens themselves, and the role of the immune system and the pathogenicity of antibodies and T cells are currently under study. Animal models are a promising tool for testing these various hypotheses and helping to elucidate the pathogenesis of autoimmunity as well as the autoimmune trigger.
Animal models as tools for understanding the etiology of SCLC-associated autoimmunity
As outlined above, the underlying causes of SCLC-related autoimmunity and how it leads to pathology remain poorly understood despite many years of investigation. The rapid progression of SCLC coupled with the rarity of the related autoimmune diseases make studies in human patients challenging. Animal models can be extremely helpful for the investigation of disease development and progression; they allow many analyses that are difficult or impossible to carry out in human patients.
Generating animal models that accurately represent human SCLC-associated paraneoplastic neurological syndromes has been very challenging. For example, the passive transfer or intraventricular injection of anti-Yo antibodies from patients with PCD (Table 1) into mice and rats did not induce disease in the animals [122, 123]. When HuD was used as either a protein or DNA to immunize mice, a strong anti-Hu response and high titers of T cell inflammatory infiltrates were observed in all immunized animals [110, 111]. Although some insight into the anti-Hu immune response was gained from these studies, these animals did not develop neurological symptoms or neuropathological abnormalities. The transfer of autoreactive T cells against the PNMA1 antigen in rats resulted in no clinical signs of neurologic disease despite an inflammatory response in the brains of the animals [124]. More recently, two mouse models with immunologically induced retinopathy associated with elevated recoverin antibodies were developed. In one case, mice were immunized with recombinant recoverin three times. In the other, mice were injected with hybridoma cells that produce a monoclonal antibody targeting recoverin. In both models, retinopathy was observed, suggesting that this kind of approach can be used to mimic this particular type of autoimmunity [125]. In another recent study, stiff person syndrome-like symptoms were induced in rats through repetitive intrathecal application of anti-amphiphysin IgG antibodies, including stiffness of trunk and limb muscles, muscle spasms, and gait abnormalities [126]. One weakness of all the aforementioned models is that immunogenicity was induced by exogenous introduction of antigens or antibodies and not by the "natural" presence of SCLC. The development of a SCLC animal model and the study of its associated immune response would provide a better model system for SCLC-associated PNS.
Creating a SCLC animal model has not been easy. Expression of proneural transcription factor human achaete-scute homolog-1 (hASH-1), which is highly expressed in SCLC, under the control of the bronchial epithelial-expressed Clara cell CC10 promoter in mice was not successful. Even though these mice exhibited rapid hyperplasia after being crossed with a transgene CC10-SV40 large T antigen, they developed adenocarcinomas that did not resemble human SCLC [127]. Other attempts have been made using xenograft models with SCLC cell lines or primary SCLC tumors [128–130]. However, these strategies require immune-compromised animals, thereby limiting their utility for studies of autoimmunity. Success was finally achieved through the conditional knockout of the Rb and Trp53 genes in the lungs of mice [131, 132]. The inactivation of both genes is commonly found during lung cancer pathogenesis and has been identified in up to 90% of human SCLCs [4, 133]. Using a Cre-loxP system, "floxed" Rb1 and Trp53 can be homozygously deleted in the lung epithelium of transgenic mice through intratracheal instillation of Adeno-Cre virus. All treated mice develop multiple tumors with histopathology and immunophenotype similar to human SCLC beginning around 200 days post infection [131, 132]. The prolonged lag time allows for the monitoring of potential immune responses against various SCLC-related autoantigens prior to the clinical detection of the disease. Recently, it was observed that the loss of p130, a cell cycle inhibitor related to Rb[134] that normally suppresses SCLC development [135], accelerates the development of SCLC in Rb/Trp53-mutant mice. Rb/Trp53/p130 mutant mice may thus provide an alternative mouse model of SCLC with a shortened lag time [136].
Our laboratory examined the anti-Hu response in the inducible Rb/Trp53 knock out mouse model system [48]. Just like their human counterparts, tumors derived from the SCLC mouse model expressed Hu proteins. Interestingly, elevated anti-Hu antibodies were detected in 14% of SCLC-prone mice, similar to the frequency of above background anti-Hu response in human SCLC patients. Furthermore, the pattern of reactivity against the Hu protein family and Hu deletion constructs was similar to that observed in human patients [45–47], supporting the notion that the N-terminal part of the protein containing RRM1 may contain the epitopes that bind to MHC and may be the key target of the autoimmune response. Thus, this mouse model system closely mimics previously observed aspects of the anti-Hu response in human SCLC patients.
Anti-Hu reactivity relative to SCLC detection and image-based screening of SCLC-prone mice. (A) Anti-Hu reactivity was detected 40-100 days prior to clinical detection of SCLC. Graphs from the six highly positive mice are shown. The dotted line represents the date of first clinical detection of tumor by CT scan and/or luminescence detection. The titer was determined by the highest fold dilution of plasma or serum in which there was a positive Western blot signal against recombinant HuD protein. The time (in days) between the measurement of a titer above background (titer > 5000) and clinical detection is indicated by a horizontal bar. SCLC tumor was not detected in mouse 489556, though the mouse became very sick. Mouse 509631 was sacrificed at the time of high titer detection, and the lungs of this animal showed neuroendocrine lesions in situ, but cancer was not detected. Crosses indicate dates of sacrifice. Titer values are in thousands. (B-E) Mice carrying homozygously floxed p53 and Rb alleles, as well as a luciferase reporter under the control of a β-actin promoter, were infected with adenovirus carrying the Cre recombinase gene via intratracheal instillation. Mice were monitored for tumor formation using bioluminescence detection (B, C, left panels, and D), X-ray based CT-scan (B and C, right panels, open circles, heart; arrowheads, tumor mass), and clinical symptoms like weight loss (E), altered coat, or kyphosis. B-E show the follow up of mouse 484305 which showed anti-Hu reactivity with a titer of 80,000 at 180 days (arrows) after Adeno-Cre infection. At that time, tumor was undetectable by imaging techniques (images taken 203 and 256 days after Adeno-Cre infection) (B). Tumor became detectable 256 days after Adeno-Cre infection (C). Acute weight loss was observed 286 days after Adeno-Cre infection (E). (Reprinted from [48], with permission from Elsevier, License Number 2460341062344).
The SCLC mouse model may also shed light on whether the induced autoantibodies antagonize cancer progression. This is still a topic of debate in human patients [28, 31, 41, 42, 50, 52, 88, 137–144]. In humans, some studies have noted a correlation between the presence of the autoantibodies and indolent tumor growth [42, 88, 138]. Interestingly, in our initial small study with SCLC-prone mice, we did observe one mouse that was highly positive for anti-Hu autoantibodies yet lacked an overt tumor [48]. While we did not detect a survival benefit of an anti-Hu response in the initial mouse study, we estimate that about 180 mice would be needed to clearly show the presence or absence of an effect of the anti-Hu response on survival [48].
In conclusion, the SCLC mouse model offers a highly promising new window onto the development and consequences of SCLC-related autoimmunity. To date, only anti-Hu reactivity has been examined in this model system, and it will be of great interest to test these mice for other types of antibodies, such as those listed in Table 1. Most importantly, the SCLC-prone mouse model will lend itself to mechanistic studies of the immune response and its timing relative to cancer onset. It will also be a great tool to examine potential clinical applications of autoantibodies and molecules targeting the autoantigens, such as imaging and therapeutic agents.
Potential clinical applications of SCLC-related autoantibodies and their antigens
Conclusions
Identifying SCLC-associated autoantigens that may elicit an antibody-based immune response may yield new methods for SCLC detection, screening, treatment, and imaging. Antibody responses against a wide variety of antigens are seen in SCLC patients. How common these antibodies are in patients and what the background response is in healthy individuals varies by antigen. The exact mechanism whereby these antibodies develop remains to be elucidated. While the examination of antibodies for a single autoantigen as a diagnostic or screening tool for SCLC would not be sufficiently sensitive given the fact that only a fraction of SCLC patients shows a response to any given antigen, in theory, a panel of antigens might be used to detect antibodies in the blood of those at most risk for SCLC. It is unclear whether such a panel could provide high enough sensitivity and specificity and whether the antibodies arise with enough lead time to allow intervention with an appreciable impact on survival. Effective intervention would only be possible if the tumor could be resected before it metastasizes or if improved treatments become available. Establishing the timing of an autoimmune response relative to cancer development is therefore of great importance. The identification of the autoimmune trigger (if it is distinct from the wildtype neuron-specific protein) in the different SCLC-associated PNS is crucial. Any identified epitopes might be of use as therapeutic targets, for example using tailored antibodies or synthetic molecules. A recently developed SCLC mouse model that has been shown to develop an anti-Hu response provides powerful new tool for investigation in this important field, and could provide insight into many of the questions raised above.
Declarations
Acknowledgements
The authors would like to thank the members of the Laird-Offringa lab and Andrew Gray for helpful discussions and for reviewing the manuscript. We thank Eri and Mary Lou Mettler, who have generously supported research on SCLC-associated paraneoplastic syndromes in the Laird-Offringa lab. I.A.L.O. is partially supported by Department of Defense Concept Award LC090436. The project described was supported by award number P30CA014089 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Authors’ Affiliations
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