Dataset Information

TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer.

ABSTRACT: Tumor antigen-driven selection may expand T cells having T cell receptors (TCRs) of shared antigen specificity but different amino acid or nucleotide sequence in a process known as TCR convergence. Substitution sequencing errors introduced by TCR? (TCRB) repertoire sequencing may create artifacts resembling TCR convergence. Given the anticipated differences in substitution error rates across different next-generation sequencing platforms, the choice of platform could be consequential. To test this, we performed TCRB sequencing on the same peripheral blood mononuclear cells (PBMC) from individuals with cancer receiving anti-CTLA-4 or anti-PD-1 using an Illumina-based approach (Sequenta) and an Ion Torrent-based approach (Oncomine TCRB-LR). While both approaches found similar TCR diversity, clonality, and clonal overlap, we found that Illumina-based sequencing resulted in higher TCR convergence than with the Ion Torrent approach. To build upon this initial observation we conducted a systematic comparison of Illumina-based TCRB sequencing assays, including those employing molecular barcodes, with the Oncomine assay, revealing differences in the frequency of convergent events, purportedly artifactual rearrangements, and sensitivity of detection. Finally, we applied the Ion Torrent-based approach to evaluate clonality and convergence in a cohort of individuals receiving anti-CTLA-4 blockade for cancer. We found that clonality and convergence independently predicted response and could be combined to improve the accuracy of a logistic regression classifier. These results demonstrate the importance of the sequencing platform in assessing TCRB convergence.

SUBMITTER: Looney TJ

PROVIDER: S-EPMC6962348 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer.

Looney Timothy John TJ Topacio-Hall Denise D Lowman Geoffrey G Conroy Jeffrey J Morrison Carl C Oh David D Fong Lawrence L Zhang Li L

Frontiers in immunology 20200109

Tumor antigen-driven selection may expand T cells having T cell receptors (TCRs) of shared antigen specificity but different amino acid or nucleotide sequence in a process known as TCR convergence. Substitution sequencing errors introduced by TCRβ (TCRB) repertoire sequencing may create artifacts resembling TCR convergence. Given the anticipated differences in substitution error rates across different next-generation sequencing platforms, the choice of platform could be consequential. To test th ...[more]

PMID: 31993050

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Project description:BackgroundPseudoprogression (PsPD) is a rare response pattern to immune checkpoint inhibitor (ICI) therapy in oncology. This study aims to reveal imaging features of PsPD, and their association to other relevant findings.MethodsPatients with PsPD who had at least three consecutive cross-sectional imaging studies at our comprehensive cancer center were retrospectively analyzed. Treatment response was assessed according to immune Response Evaluation Criteria in Solid Tumors (iRECIST). PsPD was defined as the occurrence of immune unconfirmed progressive disease (iUPD) without follow-up confirmation. Target lesions (TL), non-target lesions (NTL), new lesions (NL) were analyzed over time. Tumor markers and immune-related adverse events (irAE) were correlated.ResultsThirty-two patients were included (mean age: 66.7 ± 13.6 years, 21.9% female) with mean baseline STL of 69.7 mm ± 55.6 mm. PsPD was observed in twenty-six patients (81.3%) at FU1, and no cases occurred after FU4. Patients with iUPD exhibited the following: TL increase in twelve patients, (37.5%), NTL increase in seven patients (21.9%), NL appearance in six patients (18.8%), and combinations thereof in four patients (12.5%). The mean and maximum increase for first iUPD in sum of TL was 19.8 and 96.8 mm (+ 700.8%). The mean and maximum decrease in sum of TL between iUPD and consecutive follow-up was - 19.1 mm and - 114.8 mm (-60.9%) respectively. The mean and maximum sum of new TL at first iUPD timepoint were 7.6 and 82.0 mm respectively. In two patients (10.5%), tumor-specific serologic markers were elevated at first iUPD, while the rest were stable or decreased among the other PsPD cases (89.5%). In fourteen patients (43.8%), irAE were observed.ConclusionsPsPD occurred most frequently at FU1 after initiation of ICI treatment. The two most prevalent reasons for PsPD were TL und NTL progression, with an increase in TL diameter commonly below + 100%. In few cases, PsPD was observed even if tumor markers were rising compared to baseline. Our findings also suggest a correlation between PsPD and irAE. These findings may guide decision-making of ICI continuation in suspected PsPD.

Dataset Information

TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer.

Publications

TCR Convergence in Individuals Treated With Immune Checkpoint Inhibition for Cancer.

Similar Datasets

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