Biology subjects

Ahrenfeldt, J.

Publications and source records attributed to Ahrenfeldt, J..

4 recordsLinked to original sources

bioRxiv2024

Comprehensive characterization of the T cell receptor repertoire in bladder cancer

T cells are one of the primary effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. Here we investigated the clinical relevance of the T cell receptor (TCR) repertoire in patients with bladder cancer. In advanced-stage bladder cancer, low pre-treatment peripheral TCR diversity was associated with worse overall survival (p=0.024), particularly when it coincided with a low fraction of circulating T cells (p=0.00049). The low-diversity TCR repertoires were dominated by expanded clones that persisted throughout treatment and disproportionately targeted latent viral infections. Longitudinal analysis revealed a reduction in TCR diversity after treatment indicating an adverse effect on the immune system. In early-stage bladder cancer, we showed that immunotherapy had a stimulatory effect on TCR diversity in patients with good outcomes. Single-cell sequencing identified most expanded clones as cytotoxic T cells, while non-expanded clones were predominantly naive T cells. Overall, our findings suggest that TCR diversity is a promising new biomarker that may offer new avenues for tailored oncological treatment to enhance clinical outcomes for bladder cancer patients.

cancer biology↗

bioRxiv2023

Endogenous viral elements constitute a complementary source of antigens for personalized cancer immunotherapy

Personalized cancer vaccines (PCVs) largely leverage neoantigens arising from somatic mutations limiting their application to patients with relatively high tumor mutational burden (TMB). This underscores the need for alternative antigens to design PCVs for low TMB cancers. To this end, we substantiate endogenous retroviral elements (EVEs) as tumor antigens through large-scale genomic analyses of healthy tissues and solid cancers. These analyses revealed that the breadth of EVE expression in tumors stratify checkpoint inhibitor treated melanoma patients into groups with differential overall and progression-free survival. To enable the design of PCVs containing EVE-derived epitopes with therapeutic potential, we developed a computational pipeline, ObsERV. We show that EVE-derived peptides are presented as epitopes on tumors and can be predicted by ObsERV. Preclinical testing of ObsERV demonstrates induction of sustained poly-functional CD4+ and CD8+ T-cell responses as well as long-term tumor protection. As such, EVEs may facilitate and improve PCVs especially for low-TMB patients.

cancer biology↗

bioRxiv2022

The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy

Immunotherapy has revolutionised cancer treatment. However, not all cancer patients benefit, and current stratification strategies based primarily on PD1 status and mutation burden is far from perfect. We hypothesised that high activation of an innate response relative to the adaptive response may prevent proper tumour neoantigen identification and decrease the specific anticancer response, both in the presence and absence of immunotherapy. To investigate this, we obtained transcriptomic data from three large publicly available cancer datasets, the Cancer Genome Atlas (TCGA), the Hartwig Medical Foundation (HMF), and a recently published cohort of metastatic bladder cancer patients treated with immunotherapy. To analyse immune infiltration into bulk tumours, we developed an RNAseq-based model based on previously published definitions to estimate the overall level of infiltrating innate and adaptive immune cells from bulk tumour RNAseq data. From these, the adaptive-to-innate immune ratio (A/I ratio) was defined. A meta-analysis of 32 cancer types from TCGA overall showed improved overall survival in patients with an A/I ratio above median (Hazard ratio (HR) females 0.73, HR males 0.86, P < 0.05). Of particular interest, we found that the association was different for males and females for eight cancer types, demonstrating a gender bias in the relative balance of the infiltration of innate and adaptive immune cells. For patients with metastatic disease, we found that responders to immunotherapy had a significantly higher A/I ratio than non-responders in HMF (P = 0.036) and a significantly higher ratio in complete responders in a separate metastatic bladder cancer dataset (P = 0.022). Overall, the adaptive-to-innate immune ratio seems to define separate states of immune activation, likely linked to fundamental immunological reactions to cancer. This ratio was associated with improved prognosis and improved response to immunotherapy, demonstrating potential relevance to patient stratification. Furthermore, by demonstrating a significant difference between males and females that associates with response, we highlight an important gender bias which likely has direct clinical relevance.

bioinformatics↗

bioRxiv2019

Large scale automated phylogenomical analysis of bacterial whole-genome isolates and the Evergreen platform

Public health authorities whole-genome sequence thousands of pathogenic isolates each month for microbial diagnostics and surveillance of pathogenic bacteria. The computational methods have not kept up with the deluge of data and need for real-time results. We have therefore created a bioinformatics pipeline for rapid subtyping and continuous phylogenomic analysis of bacterial samples, suited for large-scale surveillance. To decrease the computational burden, a two level clustering strategy is employed. The data is first divided into sets by matching each isolate to a closely related reference genome. The reads then are aligned to the reference to gain a consensus sequence and SNP based genetic distance is calculated between the sequences in each set. Isolates are clustered together with a threshold of 10 SNPs. Finally, phylogenetic trees are inferred from the non-redundant sequences and the clustered isolates are placed on a clade with the cluster representative sequence. The method was benchmarked and found to be accurate in grouping outbreak strains together, while discriminating from non-outbreak strains. The pipeline was applied in Evergreen Online, which processes publicly available sequencing data from foodborne bacterial pathogens on a daily basis, updating the phylogenetic trees as needed. It has so far placed more than 100,000 isolates into phylogenies, and has been able to keep up with the daily release of data. The trees are continuously published on https://cge.cbs.dtu.dk/services/Evergreen

bioinformatics↗