Cutting edge: unconventional CD8+ T cell recognition of a naturally occurring HLA-A*02:01-restricted 20mer epitope

Unconventional HLA class I-restricted CD8+ T cell epitopes, longer than 10 aa, have been implicated to play a role in human immunity against viruses and cancer. T cell recognition of long peptides, centrally bulging from the HLA cleft, has been described previously. Alternatively, long peptides can contain a linear HLA-bound core peptide, with a N- or C-terminal peptide "tail" extending from the HLA peptide binding groove. The role of such a peptide "tail" in CD8+ T cell recognition remains unclear. In this study, we identified a 20mer peptide (FLPTPEELGLLGPPRPQVLA [FLP]) derived from the IL-27R subunit α gene restricted to HLA-A*02:01, for which we solved the crystal structure and demonstrated a long C-terminal "tail" extension. FLP-specific T cell clones demonstrated various recognition modes, some T cells recognized the FLP core peptide, while for other T cells the peptide tail was essential for recognition. These results demonstrate a crucial role for a C-terminal peptide tail in immunogenicity. </p

Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain

Background: The immunoglobulin J chain (Jchain) is highly expressed in the majority of multiple myeloma (MM), and Jchain-derived peptides presented in HLA molecules may be suitable antigens for T-cell therapy of MM. Methods: Using immunopeptidomics, we identified Jchain-derived epitopes presented by MM cells, and pHLA tetramer technology was used to isolate Jchain-specific T-cell clones. Results: We identified T cells specific for Jchain peptides presented in HLA-A1, -A24, -A3, and -A11 that recognized and lysed JCHAIN-positive MM cells. TCRs of the most promising T-cell clones were sequenced, cloned into retroviral vectors, and transferred to CD8 T cells. Jchain TCR T cells recognized target cells when JCHAIN and the appropriate HLA restriction alleles were expressed, while JCHAIN or HLA-negative cells, including healthy subsets, were not recognized. Patient-derived JCHAIN-positive MM samples were also lysed by Jchain TCR T cells. In a preclinical in vivo model for established MM, Jchain-A1, -A24, -A3, and -A11 TCR T cells strongly eradicated MM cells, which resulted in 100-fold lower tumor burden in Jchain TCR versus control-treated mice. Conclusions: We identified TCRs targeting Jchain-derived peptides presented in four common HLA alleles. All four TCRs demonstrated potent preclinical anti-myeloma activity, encouraging further preclinical testing and ultimately clinical development.Proteomic

PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer

Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic 'cold' ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity in vitro and in vivo. The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2 '-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Mucopolysaccharidosis type I (MPS I): Assessment of disease severity, therapeutic options and early diagnosis

Bepaalde stoffen in bloed en urine, zogeheten biomarkers, kunnen gebruikt worden voor het stellen van de diagnose van de stofwisselingsziekte Mucopolysaccharidose type I (MPS I) op basis van bloed afgenomen bij de hielprikscreening. Dit blijkt uit het onderzoek van Minke de Ru dat zich richtte op het bereiken van overeenstemming tussen behandelaars over de twee behandelingsvormen van MPS I, het beter onderscheiden van de verschillende varianten van de ziekte en het vroegtijdig diagnosticeren ervan. Opname van MPS I in nationale hielprikscreeningsprogramma’s kent meerdere voordelen, maar ook ethische dilemma’s. De Ru toont tevens aan dat de biomarkers ook een rol kunnen spelen in het beoordelen van het effect van behandeling en het beter onderscheiden van de verschillende varianten van de ziekte. MPS I is een zeldzame stofwisselingsziekte, waarbij het lichaam niet in staat is bepaalde suikerketens af te breken. Door toenemende stapeling hiervan in het lichaam ontstaat een grote verscheidenheid aan ziekteverschijnselen. De ziekte is soms ernstig (ziekte van Hurler), soms relatief mild (ziekte van Scheie). Het vroeg stellen van een diagnose is vaak lastig, maar essentieel voor het behalen van een zo optimaal mogelijk behandelingsresultaat

Warthin's tumour and smoking.

Item does not contain fulltextOBJECTIVE: In an evaluation of our patients with parotid gland neoplasms, we noticed that patients with a Warthin's tumour were heavy smokers. The aim of this study was to confirm earlier findings in the literature concerning a possible association between smoking and the development of a Warthin's tumour. METHODS: A case control study was performed using the clinical records and discharge letters of all consecutive patients with a Warthin's tumour in the pathology database of our hospital covering the last 15 years. Patients with a pleomorphic adenoma and a group of patients visiting our audiology department were used as controls. RESULTS: A smoking history was found in 97.5% of the patients with a Warthin's tumour. Of the patients with a pleomorphic adenoma, 59% had a smoking history; 56.5% of the audiology group had a smoking history. Mean age at the time of the operation was 60.1 years of age in the Warthin's tumour group and 48.6 for the pleomorphic adenoma group. CONCLUSION: The mean age for the development of a Warthin's tumour is ten years older than for a pleomorphic adenoma. Furthermore, the development seems to be closely related to smoking habits