Biology subjects

McCann, K. J.

Publications and source records attributed to McCann, K. J..

5 recordsLinked to original sources

bioRxiv2025

The Origin, Diagnosis, and Prognosis of Oligomannose-Type Diffuse Large B Cell Lymphoma

The acquisition of N-glycosylation sites occupied by oligomannose-type glycans in the immunoglobulin complementarity-determining region (CDR) is an early clonal tumor-specific identifier of follicular lymphoma (FL). CDR-located N-glycosylation sites are also acquired in germinal-center-B-cell-like diffuse large B-cell lymphomas (GCB-DLBCL), but their significance is less defined. We used RNA-seq immunoglobulin assembly to determine the frequency and CDR location of the acquired N-glycosylation sites (AGS) in two large independent DLBCL cohorts. Composition of the glycans occupying the AGS was determined using liquid chromatography-mass spectrometry and correlated with cell-of-origin, FL signature (defined by EZB phenotype or BCL2 translocation), transcript profile, and clinical outcome. CDR-located AGS were observed in 41-46% of GCB-DLBCL but were rare in other DLBCL. Only CDR-located AGS of DLBCL with an FL signature were occupied by oligomannose-type glycans. These DLBCL were termed Mann-type DLBCL. Conversely, the AGS of the other DLBCL were either non-glycosylated or occupied by complex-type glycans. Mann-type status was an independent marker of short progression-free survival and overall survival. In contrast, the other GCB-DLBCL cases, including those with an FL signature but without AGS, had the best outcomes. Mann-type DLBCL overexpressed gene-sets of cell growth, survival, and cycling, and underexpressed proinflammatory and apoptotic pathways, irrespective of concomitant MYC translocations. Acquisition of Mann-type glycans is a highly selective environmental pressure, identifying the most aggressive GCB-DLBCL with an origin related to FL. The detection of AGS in the CDR of GCB-DLBCLs with a BCL2 translocation defines Mann-type DLBCLs, refines prognosis and marks a precise tumor interaction to block early therapeutically. Key pointsO_LIAcquisition of Mann-type glycans is a tumor-specific environmental pressure identifying the most aggressive GCB-DLBCL with an origin related to FL. C_LIO_LIMann-type DLBCL can be diagnosed by the concomitant detection of AGS in the CDR and a BCL2 translocation. C_LI

cancer biology↗

bioRxiv2024

Comparative analysis of protein expression between oesophageal adenocarcinoma and normal adjacent tissue

Oesophageal adenocarcinoma (OAC) is the 7th most common cancer in the United Kingdom and remains a significant health challenge. This study presents a proteomic analysis of seven OAC donors complementing our previous neoantigen identification study of their human leukocyte antigen (HLA) immunopeptidomes. Using label-free mass spectrometry proteomics, we compared OAC tumour tissue to matched normal adjacent tissue (NAT) to identify differentially expressed proteins. We identified differential expression of a number of proteins previously linked to OAC and other cancers. We observed enrichment of processes and pathways relating RNA processing and the immune system. Our findings also offer insight into the role of the protein stability in the generation of the neoantigen we previously identified. These results provide independent corroboration of existing oesophageal adenocarcinoma biomarker studies that may inform future diagnostic and therapeutic research.

cancer biology↗

bioRxiv2024

Comparative analysis of transcriptomic and proteomic expression between two non-small cell lung cancer subtypes

Non-small cell lung cancer (NSCLC) is frequently diagnosed at an advanced stage and has poor survival. NSCLC subtypes require different treatment regimes, hence there are extensive efforts to find more precise and non-invasive differential diagnostics tools. Complementing these efforts, we examined two NSCLC subtypes for differences that may inform treatment options and identify potential novel therapeutic pathways. Here we present a comparative analysis of transcriptomic and proteomic expression in tumours from a cohort of 22 NSCLC patients: 8 squamous cell carcinoma (LUSC), 14 adenocarcinoma (LUAD). We examined differential gene and differential protein expression between LUSC and LUAD, and between NSCLC subtypes and either PBMCs or normal adjacent lung tissue (NAT). We found that both NSCLC subtypes shared common differences in gene expression to PBMC relating to developmental and structural changes, and common protein expression differences to NAT relating to protein translation and RNA related processing and splicing. Between NSCLC subtypes we found differential gene expression relating to cell differentiation for LUSC and cellular structure and immune response regulation for LUAD. Differential protein expression between NSCLC subtypes related to extracellular structure for LUSC and metabolic processes, including glucose metabolism for LUAD. Many of our observations of differentially expressed genes and proteins between NSCLC subtypes support and inform existing observations, aiding both basic and clinical research seeking to identify subtype biomarkers or druggable targets.

cancer biology↗

bioRxiv2024

Proteogenomics guided identification of functional neoantigens in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) has poor survival even with modern checkpoint inhibitor therapies. Personalised vaccines based on short peptide neoantigens containing tumour mutations are an attractive precision medicine strategy, but identifying therapeutically relevant neoantigens remains challenging, with existing methods yielding positive responses in only 6% of candidates tested. We developed an immunopeptidomics approach to improve neoantigen identification in 24 NSCLC patients (15 adenocarcinoma, 9 squamous cell carcinoma). We directly identified one neoantigen and using whole exome sequencing, transcriptomics and mass spectrometry-based immunopeptidomics, we filtered predicted neoantigens based on observed cohort HLA peptide presentation. This approach achieved positive functional responses in 5 of 6 patients tested (83% success rate) with 13% of putative neoantigens (9 out of 70) eliciting strong responses. Bayesian modelling of our initial rules-based neoantigen selection further revealed patient specific peptide presentation patterns and propensities. Our findings demonstrate that incorporating donor specific HLA peptide presentation data substantially improves neoantigen identification success rates and immune response specificity, advancing personalised cancer vaccine development.

immunology↗

bioRxiv2022

Identification of neoantigens in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) has a relatively poor long-term survival and limited treatment options. Promising targets for immunotherapy are short peptide neoantigens containing tumor mutations, presented to cytotoxic T-cells by human leukocyte antigen molecules (HLA). Despite an association between putative neoantigen abundance and therapeutic response across cancers, immunogenic neoantigens are challenging to identify. Here we characterized the mutational and immunopeptidomic landscapes of tumors from a cohort of seven patients with EAC. We directly identified one HLA-I presented neoantigen from one patient, and report functional T-cell responses from a predicted HLA-II neoantigen in a second patient. The predicted class II neoantigen contains both HLA I and II binding motifs. Our exploratory observations are consistent with previous neoantigen studies in finding that neoantigens are rarely directly observed, and an identification success rate following prediction in the order of 10%. However, our identified putative neoantigen is capable of eliciting strong T-cell responses, emphasizing the need for improved strategies for neoantigen identification.

cancer biology↗