23 Evidence for antigen-driven TCRB chain convergence in the tumourinfiltrating t cell repertoire of 148 research subjects with melanoma
Year: 2018
Type: article
Study design: Observational Study
Abstract: ABSTRACT Introduction T cell convergence refers to the phenomenon whereby antigen-driven selection enriches for T cell receptors having a shared antigen specificity but different amino acid or nucleotide sequence. T cell recruitment and expansion within the tumour microenvironment (TME) may be directed by responses to tumour neoantigen, suggesting that elevated T cell convergence could be a general feature of the tumour infiltrating T cell repertoire. Here we evaluate evidence for T cell convergence within tumour biopsy and peripheral blood leukocytes (PBL) from a set of 148 research subjects with melanoma. Material and methods Total RNA from 85 tumour biopsy research samples (non-FFPE) was extracted for use in long-amplicon TCRB chain sequencing (mean amplicon length of 330 bp covering CDR1, 2 and 3) via the Oncomine TCR Beta-LR Research Assay. To evaluate T cell convergence within each biopsy, we searched for instances where TCRB chains were identical in amino acid space (shared variable gene identity and CDR3 amino acid sequence) but had distinct nucleotide sequences owing to N-addition and exonucleotide chewback within the V-D and D-J junctions of the CDR3. To provide context, we evaluated evidence for T cell convergence in PBL T cell repertoires derived from healthy donors and 63 additional individuals with melanoma. Results and discussions Sequencing of melanoma biopsy research samples yielded an average of 6029 clones per sample. 11 of 85 samples yielded fewer than 100 clones and were eliminated from downstream analysis. Convergent T cell receptors were identified in 68/74 (92%) of tumour infiltrating T cell repertoires having greater than 100 detected clones. The frequency of convergent T cell rearrangements was greater in melanoma tumour biopsies than healthy or melanoma PBL samples. Conclusion These data suggest that T cell convergence may be a common feature of the melanoma infiltrating T cell repertoire. Convergence was more frequently observed within the TME than T cell repertoires derived from healthy and melanoma PBL, consistent with elevated antigen-driven T cell selection within the TME. The extent to which convergence is a feature of the TME in other cancers is not yet known. T cell receptor convergence may be driven by T cell responses to tumour neoantigen within the TME. In such case, in silico identification of convergent T cell receptors by long-amplicon TCRB sequencing may serve as a means for rapid identification of antigen-specific T cell receptors for future therapeutic use.
Source: ESMO Open
Authors: T. Looney, L. Miller, G. Lowman, E. Linch, J. Zheng, D. Topacio-Hall
Institution: Thermo Fisher Scientific (United States)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,910
OpenAlex ID: W2811264736