New spotlight: Changes in T-cell Receptor Repertoire Predict Chemoradiotherapy Outcomes In Cancer
T-cell receptor determinants of response to chemoradiation in locally-advanced HPV16-driven malignancies.
Introduction
Nenclares et al (2024) utilise a combinational approach to monitor the effect of chemoradiotherapy (CRT) on peripheral T-Cell receptors (TCR).
CRT is a gold standard treatment for HPV-related tumour progression such as that noted in cervical carcinomas (CC), Head and Neck Squamous Cell Carcinoma (HNSCC) and Anal Squamous Cell Carcinoma (ASCC) by promoting anti-tumour immune responses including cytotoxic T-Cell activation.
Spatial assessment between tumour and peripheral T-cell makeup allowed for the prediction of treatment outcome.
Main Points
- The effects of CRT have been shown to be positive on the most part in abating the growth of tumours but despite this there are relapses post-treatment showing the need for further investigation into the driving forces of tumour development.
- TCR changes can be monitored via the viral oncogenic protein expressed by Human papillomavirus (HPV)- driven tumours.
- The diversity, clonality and degree of sequence similarity of the TCR repertoire were characterized with associations between different metrics and response to CRT assessed.
- TCR sequencing of complementarity-determining region 3 of the b-chain (CDR3ß) in both the pre-treatment tumor-infiltrating lymphocytes (TILs) and PBMCs derived from both pre and post treatment samples allows for in-depth assessment of the tumour environment interactions and is deployed to monitor T-cell clonal populations during treatment of CRT to link these with patient response.
- A combinational approach using the sequencing data and in-silico assessment derived from statistical analysis (lymphoSeq R package) gives a rounded view of the effect on clonal populations.
- Clonal relatedness evaluates the relationship between CRT response and peripheral clonotypes. A significant increase clonal relatedness was noted in responders at 6 weeks in comparison to baseline.
- HLA-typing of individuals used to compartmentalise clusters identified through in-silico analysis to predict CDR3ß binding with HPV16 peptide clusters.
- Clonotype clustering analysis using tumour and peripheral TCR repertoire revealed that responders were predictive of significantly increased CDR3ß clustering in expanded TCR clones.
Conclusion
The authors utilised a multi-faceted method which included applying sequencing data to those in-silico analysis to elucidate the mechanisms of action that may control immune responses to treatment of CRT. This allowed for novel predictive markers responding to CRT generated from intra and peripheral TCR metrics and in-silico clones, giving scope for more appropriate patient stratification.
EPISTEM SERVICES
Epistem is a GCLP-accredited laboratory specialising in assessing biomarker, target discovery and personalised medicine to inform drug development and clinical studies. We regularly employ multi-omic assessment studies which cover a wide spectrum of tissues and cells. We specialise in extract RNA from challenging samples such as FFPE. We offer microarray, qPCR and NGS services for gene expression, whole exome, epigenetic analysis and T-cell receptor sequencing.
Epistem offers several pre-clinical human cancer models (including breast cancer) to assess the efficacy of cancer therapies as single agents or in combination with chemo- and/or local radio-therapy. To aid in the assessment we have a Cytation 5 live-cell imaging system and a 15 colour Novocyte flow cytometer, which gives the opportunity to evaluate treatment effects and elucidate the function of specific immune cell types in vitro and ex vivo.
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