Mazlina Ismail

University College London

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Benny Chain

University College London

Theres Oakes

University College London

Imran Uddin

University College London

Gerhardt Attard

University College London

Kroopa Joshi

Royal Marsden NHS Foundation Trust

Sergio A. Quezada

CRUK Lung Cancer Centre of Excellence

James L. Reading

CRUK Lung Cancer Centre of Excellence

James Heather

Weatherford College

Charles Swanton

The Francis Crick Institute

Wout Devlies

KU Leuven

Cooperative Institutions

University College London

268

London Cancer

166

Cancer Research UK

158

CRUK Lung Cancer Centre of Excellence

152

The Francis Crick Institute

109

Royal London Hospital

Royal Marsden NHS Foundation Trust

University College Hospital

Royal Marsden Hospital

University College London Hospitals NHS Foundation Trust

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Quantitative analysis of the T cell receptor repertoire

Methods in enzymology on CD-ROM/Methods in enzymology (2019)

Imran Uddin Annemarie Woolston Thomas Peacock Kroopa Joshi Mazlina Ismail

Cancer Immunotherapy

Immune receptor

10.1016/bs.mie.2019.05.054

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Citations (14)

The T Cell Response to the Contact Sensitizer Paraphenylenediamine Is Characterized by a Polyclonal Diverse Repertoire of Antigen-Specific Receptors

Frontiers in Immunology (2017)

Theres Oakes Amy Popple Jason Williams Katharine Best James Heather

Paraphenylenediamine (PPD) is a common component of hair dyes and black henna tattoos and can cause skin sensitization and allergic contact dermatitis (ACD). The cutaneous inflammatory reaction associated with ACD is driven by both CD4+ and CD8+ T cells. However, the characteristics of such responses with respect to clonal breadth and magnitude are poorly defined. In this study, we have characterized the in vitro recall response of peripheral blood T cells prepared from PPD-allergic individuals to a PPD-human serum albumin (HSA) conjugate (PPD-HSA). Quantitative high throughput sequencing was used to characterize the changes in the repertoire of T cell receptor (TCR) α and β genes after exposure to antigen in vitro. The PPD conjugate induced expansion of T cells carrying selected TCRs, with around 800 sequences (around 1%) being 8 or more times as abundant after culture than before. The expanded sequences showed strong skewing of V and J usage, consistent with an antigen-driven clonal expansion. The complementarity-determining region 3 sequences of the expanded TCRs could be grouped into several families of related amino acid sequence, but the overall diversity of the expanded sample was not much less than that of a random sample of the same size. The results suggest a model in which PPD-HSA conjugate stimulates a broad diversity of TCRs, with a wide range of stimulation strengths, which manifest as different degrees of in vitro expansion.

Polyclonal antibodies

10.3389/fimmu.2017.00162

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Citations (13)

Publisher Correction: Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer

Nature Medicine (2020)

Kroopa Joshi Marc Robert de Massy Mazlina Ismail James L. Reading Imran Uddin

10.1038/s41591-020-0866-8

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Citations (2)

Changes in T cell receptor repertoire associated with combined variable immune-deficiency (CVID)

Mazlina Ismail Theres Matjeka Connor Husovsky James Heather Katharine Best

Common Variable Immunodeficiency

Immune receptor

Source

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Citations (0)

Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

Research Square (Research Square) (2023)

A. M. Mahedi Hasan Paolo Cremaschi Daniel Wetterskog Anuradha Jayaram Stephen Q. Wong

Abstract Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome-wide copy number profiling and bespoke approaches targeting the androgen receptor ( AR ) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR -neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations and cluster-specific AR gene architectures. Copy number boundaries identified treatment-selected clones with distinct lethal trajectories.

Copy number analysis

10.21203/rs.3.rs-1638211/v1

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Citations (1)

Benchmarking of T cell receptor repertoire profiling methods reveals large systematic biases

Nature Biotechnology (2020)

Pierre Barennes Valentin Quiniou Mikhail Shugay Evgeniy S. Egorov Alexey N. Davydov

Multiplex

10.1038/s41587-020-0656-3

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Citations (96)

Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer

Proceedings of the National Academy of Sciences (2025)

Samuel P. Pitzen Amber N. Rudenick Yinjie Qiu Weijie Zhang Sarah A. Munro

Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of RARG uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity.

Basal (medicine)

10.1073/pnas.2415308122

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Citations (0)

Author response: The naive T-cell receptor repertoire has an extremely broad distribution of clone sizes

Peter C. de Greef Theres Oakes Bram Gerritsen Mazlina Ismail James Heather

clone (Java method)

10.7554/elife.49900.sa2

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Quantitative Characterization of the T Cell Receptor Repertoire of Naïve and Memory Subsets Using an Integrated Experimental and Computational Pipeline Which Is Robust, Economical, and Versatile

Frontiers in Immunology (2017)

Theres Oakes James Heather Katharine Best Rachel Byng-Maddick Connor Husovsky

The T cell receptor (TCR) repertoire can provide a personalised biomarker for infectious and non-infectious diseases. We describe a protocol for amplifying, sequencing and analysing TCRs which is robust, sensitive and versatile. The key experimental step is ligation of a single stranded oligonucleotide to the 3' end of the TCR cDNA. This allows amplification of all possible rearrangements using a single set of primers per locus. It also introduces a unique molecular identifier to label each starting cDNA molecule. This molecular identifier is used to correct for sequence errors and for effects of differential PCR amplification efficiency, thus producing more accurate measures of the true TCR frequency within the sample. This integrated experimental and computational pipeline is applied to the analysis of human memory and naive subpopulations, and results in consistent measures of diversity and inequality. After error correction, the distribution of TCR sequence abundance in all subpopulations followed a power law over a wide range of values. The power law exponent differed between naïve and memory populations, but was consistent between individuals. The integrated experimental and analysis pipeline we describe is appropriate to studies of T cell responses in a broad range of physiological and pathological contexts.

Characterization

10.3389/fimmu.2017.01267

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Citations (105)

Copy number architectures define treatment-mediated selection of lethal prostate cancer clones

Nature Communications (2023)

A. M. Mahedi Hasan Paolo Cremaschi Daniel Wetterskog Anuradha Jayaram Stephen Q. Wong

Abstract Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR -neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance ( p -values 3.07 × 10 −8 and 6.4 × 10 −4 ). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories.

Copy number analysis

Comparative genomic hybridization

Chromothripsis

10.1038/s41467-023-40315-9

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Citations (5)