Ankylosing Spondylitis (AS) is an autoimmune disease which is mostly characterised by lower back pain and fusion of the vertebrae. Over 90% of AS patients express the HLA-B27 gene and the probability of disease increases during infection with gastrointestinal bacteria. In this study we look at how mutations in the HLA-B27 gene and infection with Salmonella impact of on its immunological function. We observed that inflammation due to infection drastically increase an abnormal form of HLA-B27, possibly leading to autoimmunity. The data collected in this study would also be valuable for interrogation of other Spondyloarthropathies.
We reported previously that in preclinical models, BMP4 is a potent inhibitor of breast cancer metastasis and that high BMP4 protein levels predict favourable patient outcomes. Here, we analysed a breast cancer xenograft with or without enforced expression of BMP4 to gain insight into the mechanisms by which BMP4 suppresses metastasis. Transcriptomic analysis of cancer cells recovered from primary tumours and phosphoproteomic analyses of cancer cells exposed to recombinant BMP4 revealed that BMP4 inhibits cholesterol biosynthesis, with many genes in this biosynthetic pathway being downregulated by BMP4. The treatment of mice bearing low-BMP4 xenografts with a cholesterol-lowering statin partially mimicked the anti-metastatic activity of BMP4. Analysis of a cohort of primary breast cancers revealed a reduced relapse rate for patients on statin therapy if their tumours exhibited low BMP4 levels. These findings indicate that BMP4 may represent a predictive biomarker for the benefit of additional statin therapy in breast cancer patients.
Abstract IntroductionAromatase inhibtors (AI) are recommended in the adjuvant management of oestrogen receptor positive (ER+) early breast cancer (EBC). With no consensus regarding the decision between starting AIs upfront or after an initial period of tamoxifen identifying factors that predict early recurrence on tamoxifen would help guide clinicians to choose the appropriate treatment strategy. HER2 overexpression and progesterone receptor (PR) negativity are poor prognostic factors in ER+ EBC. We aim to investigate whether these factors are particularly strong predictors of early recurrence.MethodsER, PR and HER2 receptor analysis was performed on a retrospective cohort of women with symptomatic early breast cancer diagnosed between 1980 – 2002 who received adjuvant tamoxifen. The primary endpoint was disease free survival (DFS) and recurrence was defined as invasive disease at any site as determined by histopathology or a high index of suspicion upon radiological investigation. Univariate and multivariate time dependent Cox regression analysis, using ≤2.5yrs as the time dependent term, were performed. The pattern of recurrence over the first five years was charted using an Epanechnikov smoothing function.ResultsA total of 402 tumours were confirmed as ER+ and therefore included in the analysis. The median age of the cohort was 63yrs with a median follow up of 6.1yrs. 241 (60.0%) of the tumours were PR+ and 51 (12.7%) were HER2 positive. On univariate analysis tumour size, grade, nodal status and PR status were significantly associated with DFS (p <0.001; except PR status, p = 0.002). In univariate time dependent analysis only HER2 status had a significant interaction with the time dependent term (p = 0.004) with a hazard ratio (HR) of 2.78 (95% CI 1.47-5.26) for DFS within the first 2.5yrs following diagnosis and a HR of 0.48 (0.18-1.34) beyond 2.5yrs. Following adjustment for pathology and PR status this interaction remained significant (p = 0.004; <2.5yrs HR 2.54 (1.21-5.32); >2.5yrs HR 0.33 (0.10-1.11)). Fig 1. clearly demonstrates a peak in the annual recurrence rate at 2yrs in the HER2 positive group.ConclusionsThis data shows that HER2 positive patients are at a significantly higher risk of recurrence within the first 2.5yrs following diagnosis of ER+ EBC. Whilst TransATAC and BIG 1-98 subgroup analysis demonstrate that HER2 is not predictive for response to AIs over tamoxifen, HER2 positive patients did show a significant reduction in recurrence on an AI in line with the remainder of the cohorts. We would therefore suggest that delaying initiation of AI therapy potentially leaves women at greater risk of early recurrence. Perhaps more importantly we should ensure that all ER positive HER2 positive patients receive trastuzumab along with their endocrine therapy as there is now significant in vitro and clinical evidence that inhibition of growth factor pathways is essential for endocrine sensitivity. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4045.
Additional file 2. Table S1. Heat map ranking the total phosphopeptide intensity for specific kinases across the 19 PDX samples. Table S2. Heat map ranking individual phosphopeptide intensity for specific kinases across the 19 PDX samples.
The association of HLA-B27 with spondyloarthropathy is one of the strongest documented for any autoimmune disease. A common hypothesis for this association is the arthritogenic peptide concept. This dictates that differences in the peptide binding preferences of disease-associated and non-disease-associated HLA-B27 allotypes underlie the presentation of bacterial and self-peptides, leading to cross-reactive T cell immunity and subsequent autoimmune attack of affected tissues. The aim of this study was to analyze and compare self-peptides from 8 HLA-B27 allotypes, to increase existing data sets of HLA-B27 ligands, to refine and compare their consensus-binding motifs, and to reveal similarities and differences in the peptide repertoire of the HLA-B27 subtypes.Qualitative differences in the peptides bound to the 8 most frequent HLA-B27 subtypes were determined by tandem mass spectrometry, and quantitative changes in allelic binding specificities were determined by highly sensitive and targeted multiple reaction monitoring mass spectrometry.We identified >7,500 major histocompatibility complex class I peptides derived from the 8 most common HLA-B27 allotypes (HLA-B*27:02 to HLA-B*27:09). We describe individual binding motifs for these alleles for the 9-12-mer ligands. The peptide repertoires of these closely related alleles showed significant overlap. Allelic polymorphisms resulting in changes in the amino acid composition of the antigen-binding cleft manifested largely as quantitative changes in the peptide cargo of these molecules.Absolute binding preferences of HLA-B27 allotypes do not explain disease association. The arthritogenic peptide theory needs to be reassessed in terms of quantitative changes in self-peptide presentation, T cell selection, and altered conformation of bound peptides.
<div>Abstract<p>Antigen recognition by CD8<sup>+</sup> T cells is governed by the pool of peptide antigens presented on the cell surface in the context of HLA class I complexes. Studies have shown not only a high degree of plasticity in the immunopeptidome, but also that a considerable fraction of all presented peptides is generated through proteasome-mediated splicing of noncontiguous regions of proteins to form novel peptide antigens. Here, we used high-resolution mass spectrometry combined with new bioinformatic approaches to characterize the immunopeptidome of melanoma cells in the presence or absence of IFNγ. In total, we identified more than 60,000 peptides from a single patient-derived cell line (LM-MEL-44) and demonstrated that IFNγ induced changes in the peptidome, with an overlap of only approximately 50% between basal and treated cells. Around 6% to 8% of the peptides were identified as <i>cis</i>-spliced peptides, and 2,213 peptides (1,827 linear and 386 <i>cis</i>-spliced peptides) were derived from known melanoma-associated antigens. These peptide antigens were equally distributed between the constitutive- and IFNγ-induced peptidome. We next examined additional HLA-matched patient-derived cell lines to investigate how frequently these peptides were identified and found that a high proportion of both linear and spliced peptides was conserved between individual patient tumors, drawing on data amassing to more than 100,000 peptide sequences. Several of these peptides showed <i>in vitro</i> immunogenicity across multiple patients with melanoma. These observations highlight the breadth and complexity of the repertoire of immunogenic peptides that can be exploited therapeutically and suggest that spliced peptides are a major class of tumor antigens.</p></div>
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