Citrullinated Epitopes Identified on Tumour MHC Class II by Peptide Elution Stimulate Both Regulatory and Th1 Responses and Require Careful Selection for Optimal Anti-Tumour Responses

BackgroundSomatic mutations or post-translational modifications of proteins result in changes that enable immune recognition. One such post-translational modification is citrullination, the conversion of arginine residues to citrulline. Citrullinated peptides are presented on MHC class II (MHCII) via autophagy which is upregulated by cellular stresses such as tumourigenesis.MethodsPeptides were eluted from B16 melanoma expressing HLA-DP4 and analysed by mass spectrometry to profile the presented citrullinated repertoire. Initially, seven of the identified citrullinated peptides were used in combination to vaccinate HLA-DP4 transgenic mice. Immune responses were characterised from the combination and individual vaccines by ex vivo cytokine ELISpot assay and assessed for tumour therapy.ResultsThe combination vaccine induced only weak anti-tumour therapy in the B16cDP4 melanoma model. Immune phenotyping revealed a dominant IFNγ response to citrullinated matrix metalloproteinase-21 peptide (citMMP21) and an IL-10 response to cytochrome p450 peptide (citCp450). Exclusion of the IL-10 inducing citCp450 peptide from the combined vaccine failed to recover a strong anti-tumour response. Single peptide immunisation confirmed the IFNγ response from citMMP21 and the IL-10 response from citCp450 but also showed that citrullinated Glutamate receptor ionotropic (citGRI) peptide stimulated a low avidity IFNγ response. Interestingly, both citMMP21 and citGRI peptides individually, stimulated strong anti-tumour responses that were significantly better than the combined vaccine. In line with the citGRI T cell avidity, it required high dose immunisation to induce an anti-tumour response. This suggests that as the peptides within the combined vaccine had similar binding affinities to MHC-II the combination vaccine may have resulted in lower presentation of each epitope and weak anti-tumour immunity.ConclusionWe demonstrate that tumours present citrullinated peptides that can stimulate Th1 and regulatory responses and that competition likely exists between similar affinity peptides. Characterisation of responses from epitopes identified by peptide elution are necessary to optimise selection for tumour therapy.

Extrarenal Wilms' Tumour of the Ovary

Wilms' tumour (nephroblastoma) is the most common abdominal malignancy in children. Extrarenal Wilms' tumour (ERWT) is rare, with limited reports in the literature. Hereby, we report a case of unilateral ovarian Wilms' tumour, which was diagnosed initially by closed biopsy and confirmed later by histopathology study of the excised tumour. We are discussing the unusual location and presentation of Wilms' tumour and showing the medical challenges in both the initial clinical impression and the pathological diagnosis. Demonstrating therapeutic plans and showing the good outcome achieved by using the classic renal Wilms’ tumour therapy protocols. Keywords: Extrarenal tumour; Wilms' tumour; nephroblastoma; Ovary; paediatric tumour.

Biomaterial-based strategies for maxillofacial tumour therapy and bone defect regeneration

Issues caused by maxillofacial tumours involve not only dealing with tumours but also repairing jaw bone defects. In traditional tumour therapy, the systemic toxicity of chemotherapeutic drugs, invasive surgical resection, intractable tumour recurrence, and metastasis are major threats to the patients’ lives in the clinic. Fortunately, biomaterial-based intervention can improve the efficiency of tumour treatment and decrease the possibility of recurrence and metastasis, suggesting new promising antitumour therapies. In addition, maxillofacial bone tissue defects caused by tumours and their treatment can negatively affect the physiological and psychological health of patients, and investment in treatment can result in a multitude of burdens to society. Biomaterials are promising options because they have good biocompatibility and bioactive properties for stimulation of bone regeneration. More interestingly, an integrated material regimen that combines tumour therapy with bone repair is a promising treatment option. Herein, we summarized traditional and biomaterial-mediated maxillofacial tumour treatments and analysed biomaterials for bone defect repair. Furthermore, we proposed a promising and superior design of dual-functional biomaterials for simultaneous tumour therapy and bone regeneration to provide a new strategy for managing maxillofacial tumours and improve the quality of life of patients in the future.

Engineering Disulphide-Free Autonomous Antibody VH Domains to modulate intracellular pathways

An attractive approach to target intracellular macromolecular interfaces is to design small high affinity proteins. In this manuscript a stable, autonomous, human derived non-immunogenic, disulphide-free VH domain, has been engineered for intracellular expression studies. VH domains can be designed to possess a large dynamic repertoire of binders, as opposed to other scaffolds types that are highly rigid and possess fewer sites of random variation. Picomolar inhibitors were identified using phage display against the eIF4F complex, which is commonly hyper-activated in many cancers. These molecules were also shown to impair cellular proliferation and to reduce the expression of malignancy related proteins. Structural characterization elucidated that these VH domains bound eIF4E at the eIF4G interaction interface via a novel binding pose. Molecules able to mimic this pose and interfere with the eIF4F complex are potentially important for wide-ranging tumour therapy applications.