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PLoS One. 2019 Mar 14;14(3):e0213684. doi: 10.1371/journal.pone.0213684. eCollection 2019.

Model to improve specificity for identification of clinically-relevant expanded T cells in peripheral blood.

Author information

1
Adaptive Biotechnologies, Seattle, Washington, United States of America.
2
Pfizer Incorporated, La Jolla, California, United States of America.
3
Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.

Abstract

Current methods to quantify T-cell clonal expansion only account for variance due to random sampling from a highly diverse repertoire space. We propose a beta-binomial model to incorporate time-dependent variance into the assessment of differentially abundant T-cell clones, identified by unique T Cell Receptor (TCR) β-chain rearrangements, and show that this model improves specificity for detecting clinically relevant clonal expansion. Using blood samples from ten healthy donors, we modeled the variance of T-cell clones within each subject over time and calibrated the dispersion parameters of the beta distribution to fit this variance. As a validation, we compared pre- versus post-treatment blood samples from urothelial cancer patients treated with atezolizumab, where clonal expansion (quantified by the earlier binomial model) was previously reported to correlate with benefit. The beta-binomial model significantly reduced the false-positive rate for detecting differentially abundant clones over time compared to the earlier binomial method. In the urothelial cancer cohort, the beta-binomial model enriched for tumor infiltrating lymphocytes among the clones detected as expanding in the peripheral blood in response to therapy compared to the binomial model and improved the overall correlation with clinical benefit. Incorporating time-dependent variance into the statistical framework for measuring differentially abundant T-cell clones improves the model's specificity for T-cells that correlate more strongly with the disease and treatment setting of-interest. Reducing background-level clonal expansion, therefore, improves the quality of clonal expansion as a biomarker for assessing the T cell immune response and correlations with clinical measures.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: JR, HR, and EY own stocks or shares and are paid employees of Adaptive Biotechnologies. HR holds patents associated with Adaptive Biotechnologies. JB, SD, TX, and CD own stocks or shares and are paid employees of Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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