Academic literature on the topic 'Tumour-associated autoantibodies'

Abstract Anti-transcription intermediary factor 1 (TIF1)-γ autoantibodies are robustly linked with cancer-associated DM in adults. This review aims to give an overview of the physiological context of TIF1-γ and to determine whether there is a pathophysiological link between anti-TIF1-γ autoantibodies and the occurrence of cancer. Detection of anti-TIF1-γ autoantibodies has a high sensitivity and specificity for cancer-associated DM in adults and is therefore useful for both diagnosis and cancer risk stratification. The function of the autoantigen, TIF1-γ, may provide insight into the mechanism behind this association. TIF1-γ is a ubiquitously present protein involved in various biological pathways, including TGF-β signalling. In cancer, it can act either as a tumour suppressor or promoter, depending on the cellular context and cancer stage. Evolving data provide pathophysiological insights, linking anti-TIF1-γ autoantibodies to both the anti-tumour response and to muscle and skin damage. TIF1-γ expression is increased in muscle and skin tissue of patients with DM. Mutations or loss-of-heterozygosity in TIF1-γ alleles in malignant tissue may result in the expression of tumour-specific neo-antigens stimulating autoantibody production. The newly formed autoantibodies are hypothesized to cross-react with antigens in muscle and skin, driving the development of DM. Based on the current evidence, anti-TIF1-γ autoantibodies should be considered warning lights of a potential tumour autoantigen and should alert the physician to the possibility of an underlying cancer.

10011 Background: Increasing evidence suggests that the B cell response in cancer patients is an important component of anti-tumour immunity. Autoantibodies targeting tumour and self-antigens may serve as biomarkers of anti-tumour and auto-immunity. As they can be measured in patient' sera, they have great potential as clinical routine biomarkers. The objective of this study was to explore if autoantibodies are associated with survival and immune related adverse events (irAE) in patients with metastatic melanoma under checkpoint inhitibor (CPI) therapy. Methods: Pre-treatment serum samples from 333 metastatic melanoma patients receiving CPI therapy at 5 European centers were retrospectively used to identify autoantibody signatures for survival and irAE. We designed a cancer immunotherapy antigen array comprising 832 autoimmune and tumour antigens as well as immune and cancer pathway proteins. Statistical tests were separately performed for patients treated with anti-CTLA4 (alone or in combination) and with anti-PD1 antibody monotherapy. Cox-regression analysis and univariate statistical tests were applied for biomarker discovery. Progression free and overall survival was measured from treatment initiation to tumor progression or death date. irAE were recorded including onset date and grade (CTC-AE). Results: For each therapy group we identified a set of autoantibody reactivities in untreated melanoma patients that were associated with the development of irAEs and/or survival. The identified autoantibodies target a diverse set of antigens comprising neoantigens (p53), cancer testis antigens (MAGEB4), paraneoplastic antigens (gephyrin), autoantigens (ribosomal proteins, Nor-90) and FGFR1. Autoantigens that correlated with irAE and survival were e.g. anti-MAGEB4 and anti-FGFR1. Elevated anti-MAGEB4 pre-treatment levels were associated with longer overall survival (p = 0.002, HR = 0.77) and the development of irAEs (p = 0.002, HR = 1.27) in ipilimumab +/- nivolumab treated patients. Higher pre-treatment anti-FGFR1 antibodies were associated with shorter survival (p = 0.008, HR = 1.27) and a lower a lower frequency of irAEs (p = 0.04, HR = 0.69) in these patients. Conclusions: We identified autoantibody targets suggesting a diverse B cell response to antigens expressed in tumours and those associated with autoimmunity. Depending on the specific antigen, the immune response towards those antigens may be associated with anti-tumour or pro-tumour responses.

Autoimmune hepatitis (AIH) is an inflammatory disorder of the liver with a wide spectrum of disease presentation, from asymptomatic elevations in liver-associated enzymes to acute liver failure. AIH is classically associated with elevated immunoglobulins and autoantibodies, although approximately 20% of patients with features of AIH lack circulating antibodies. Recently, tumour necrosis factor alpha inhibitors have been implicated in several cases of drug-induced AIH which impact treatment regimens for patients with inflammatory bowel disease (IBD). We present a case of infliximab-induced seronegative AIH responding to budesonide therapy with successful alteration of IBD treatment regimen to vedolizumab.

The autoimmune encephalopathies are a group of conditions that are associated with autoantibodies against surface neuronal proteins, which are likely to mediate the disease. They are established as a frequent cause of encephalitis. Characteristic clinical features in individual patients often allow the specificity of the underlying antibody to be confidently predicted. Antibodies against the VGKC-complex, mainly LGI1(leucine-rich glioma-inactivated 1), CASPR2 (contactin-associated protein 2), and contactin-2, and NMDA (N-methyl, D-aspartate) -receptor are the most frequently established serological associations. In the minority of cases, an underlying tumour can be responsible. Early administration of immunotherapies, and tumour removal, where it is relevant, offer the greatest chance of improvement. Prolonged courses of immunotherapies may be required, and clinical improvements often correlate well with the antibody levels. In the present article, we have summarised recent developments in the clinical and laboratory findings within this rapidly expanding field.

Cutaneous melanoma is the most aggressive type of skin cancer that is responsible for more than 80% of skin cancer-related deaths. The incidence of cutaneous melanoma, especially thin ( < 1.0 mm) melanomas, continues to increase nationally and globally. Although thick ( ≥ 4.0 mm) melanomas are correlated with a worse prognosis, thin melanomas account for the majority of melanoma deaths due to the high volume of the disease. Therefore, there is currently an urgent need to identify melanoma-associated prognostic biomarkers for the effective monitoring of patients that are predicted to have an increased risk of tumour progression. This will enable timely therapeutic intervention and ultimately decrease melanoma attributed morbidity and mortality. The utilisation of autoantibodies as melanoma-associated biomarkers is a promising avenue towards personalised medicine. Autoantibodies are generated by the adaptive immune system in cancer patients towards autologous antigens and may provide biological information of the tumour. Additionally, autoantibodies have desirable biomarker properties such as persistent concentrations and long half-lives due to a limited proteolysis and clearance from the blood. The overarching aim of this thesis was to identify serum autoantibody biomarkers from blood that are indicative of disease progression. Early-stage cutaneous melanoma patients provided a blood sample at the point of diagnosis of their primary melanoma. Follow-up data (median of 6.2 years) of melanoma progression and patient survival was then received from the Western Australian Clinical Cancer Registry. This Masters by Research thesis is comprised of 6 chapters: a literature review introducing the research topic on cutaneous melanoma and prognosis (Chapter 1), a comprehensive published literature review discussing the current evidence for the utilisation of tumour-associated autoantibodies in the prognostication of cutaneous melanoma, as well as other cancers (Chapter 2), three research results chapters (Chapters 3-5); and a final chapter with a general discussion of main findings and future perspectives (Chapter 6). A total of 104 sera were previously screened against a functional high-throughput microarray platform containing 1627 functional proteins to measure IgG autoantibody levels. Microarray autoantibody profiles were used in chapter 3 to 5. For these chapters, follow-up data (median 6.2 years, range 5.5-7.9 years) from the Clinical Cancer Registry was used to group the early-stage cutaneous melanoma cohort into a progression versus non-progression group. In chapter 3, the prognostic utility of tumour protein 53 (p53) autoantibody as a prognostic biomarker was assessed because extensive literature suggests its potential as a prognostic biomarker. Additionally, this chapter presents an extensive description of the methodology and optimisation procedure for bead-based immunoassays, which have been followed in the subsequent chapters. Carboxylated magnetic beads have been identified as the superior bead type compared to non-magnetic beads due to their decreased level of non-specific binding and were thus used for the following chapters. The microarray and bead-based immunoassay results indicated that p53 autoantibodies were found not to be of significant prognostic value as a single prognostic marker. Its prognostic value as part of a larger autoantibody panel remains to be validated. For chapters 4 to 5, previously obtained microarray data was used to identify potential prognostic autoantibodies by using an analytical approach that takes into account both the frequency and strength of signal of autoantibodies in a high-risk versus a low-risk group. In chapter 4, superoxide dismutase 1 (SOD1) autoantibodies were identified as a potential marker for melanoma progression. The subsequent investigation of SOD1 antibodies via a bead-based immunoassay has shown that SOD1 autoantibodies might be of potential significant value for the prognostication of early-stage cutaneous melanoma patients. There was, however, a degree of discordance identified between the two testing platforms. For chapter 5, the Nomogram tool, developed by the Melanoma Institute of Australia, was used to investigate whether autoantibodies detected at the point of diagnosis might be valuable in predicting whether a melanoma patient has an increased risk of developing SLN metastasis. The tumour-necrosis factor alpha-induced protein 8 (TNFAIP8) was the top prognostic marker based on the microarray data and was therefore further investigated. The subsequent bead-based immunoassay to validate the finding has shown that TNFAIP8 autoantibodies as a single biomarker has limited value in discriminating predicted high-risk from predicted low-risk patients. There was a weak correlation and a poor level of agreement identified between the two testing platforms. Finally, chapter 6 provides a general discussion of the studies covered in this thesis. The limitations of each study and suggestions for improvement are comprehensively discussed. Importantly, future avenues for the utilisation of autoantibodies as prognostic biomarkers are highlighted.

Background Cutaneous melanoma is an aggressive cancer with a high propensity to metastasise. Melanomarelated fatalities are however preventable through early detection and complete surgical excision of the primary tumour. Current screening methods for melanoma are effective but limited to the visual examination of the skin, potentially leading to a delay in diagnosis of less obvious lesions. Circulating biomarkers have been proposed to aid with early melanoma diagnosis and are easily accessible by routine blood collection. However, despite intensive scientific efforts, there are currently no blood-based biomarkers that are sufficiently sensitive for detecting melanoma at its earliest stages. Autoantibodies represent an amplified signal of tumour immunosurveillance that is measurable in patients with various cancers and detectable prior to the clinical manifestation of a tumour. Single and combinations of autoantibody biomarkers have shown potential as diagnostic biomarkers in numerous malignancies. However, the diagnostic utility of autoantibodies in melanoma is yet to be comprehensively investigated. The purpose of this thesis was therefore to identify a distinctive autoantibody signature in primary melanoma patient blood indicative of a positive disease status. Aims The initial aim of the thesis was to perform a comprehensive literature review (Chapter 2) identifying the causes of autoantibody production in cancer, indicating their biological relevance in the initial stages of carcinogenesis. Subsequently, we aimed to identify individual and combinations of suitable autoantibody biomarkers for the diagnosis of primary melanoma (Chapter 3). Finally, this thesis aimed to develop clinically applicable assays for a selection of identified autoantibodies to ascertain their diagnostic utility in primary melanoma detection (Chapter 4). Methods A total of 245 sera from primary melanoma patients and healthy volunteers were screened against a high-throughput microarray platform containing 1627 functional proteins to measure IgG autoantibody levels (Chapter 3). Data was analysed using stringent published and machinelearning methods. Pathway analysis of identified biomarkers was also undertaken. In-house Bio-Plex assays were developed and optimised for the detection of specific IgG autoantibody levels in a cohort of 104 primary melanoma patients and 104 healthy volunteers (Chapter 4). Results The literature search (Chapter 2) revealed that autoantibody production in cancer may be due to defects in tolerance and inflammation, changes in protein expression levels, altered protein structure and cellular death mechanisms. Following the high-throughput screening of primary melanoma patient and healthy control sera, a list of 139 autoantibody biomarkers with potential for melanoma diagnosis were identified (Chapter 3). The identified biomarkers were associated with major cancer-related pathways, indicating their relevance for cancer detection. To increase the overall sensitivity of melanoma detection whilst maintaining high specificity, we identified a combination of 10 autoantibody biomarkers that, as a panel, displays a sensitivity of 79%, specificity of 84% and an AUC of 0.828 for primary melanoma detection. Finally using inhouse developed bead assays for three of the biomarkers, individual biomarker sensitivities ranged from 10.6% to 18.3% at greater than 90% specificity. As a combination, the panel was able to detect melanoma with 28% sensitivity at 85% specificity. Conclusions The work presented here shows that autoantibodies may have potential as diagnostic biomarkers for melanoma. Although the causes of their production in cancer are not well understood, the literature indicates (Chapter 2) that it is the abnormal expression and/or alteration in the structure of the corresponding antigen that is most accountable for an immune response. However, failure of tolerance mechanisms, inflammation and cell death affect the context in which the antigens are presented to the immune system, initiating the production of autoantibodies. The identified biomarkers in Chapters 3 and 4 show upregulated levels in the patient cohort relative to healthy controls. As a single biomarker, autoantibodies do not appear sufficiently sensitive for melanoma detection, but in combination their overall increased sensitivity and specificity warrants further investigation in larger cohorts using clinically applicable screening platforms and assay formats that require extensive independent validation.