2020
DOI: 10.1101/2020.11.15.383786
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Sensitivity to Immune Checkpoint Blockade and Progression-Free Survival is associated with baseline CD8+T cell clone size and cytotoxicity

Abstract: Immune checkpoint blockers (ICB) exert their anti-cancer effects via CD8+ T cells, although how responses vary over sub-populations and across clones is incompletely understood. We performed single-cell RNA-sequencing of CD8+ T cells and their receptors pre and post ICB across eight patients, integrating results with bulk-sequencing data (n=169). We identify seven phenotypic subsets with divergent sensitivity to ICB, finding the effector subset demonstrates the most pronounced changes. ICB response was related… Show more

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Cited by 2 publications
(4 citation statements)
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“…Consistent with this, we found that hospitalised COVID-19 patients with mild disease had higher numbers of expanded clones in both CD4 + and CD8 + subsets (Figure 5K) and the mean clone size was higher within the CD8 + subset (Figure S5L). In keeping with the observation that expanded CD8 T cell clones show increased expression of cytotoxicity markers (Watson et al, 2020a), using a composite gene score for cytotoxicity we found that the number of expanded clones correlated with the average cytotoxicity score across all cells for that individual in both CD4 + T effector (CD4.TEFF/TEFF.prolif) and CD8 + T effector (CD8.TEFF/TEFF.prolif) populations (Figure S5M), and was higher in mild and community COVID-19 cases with reduced cytotoxicity observed in critical and severe disease (Figure 5L).…”
Section: Reduced Diversity In Cd8 + T Cell Populations On Repertoire Analysissupporting
confidence: 79%
See 1 more Smart Citation
“…Consistent with this, we found that hospitalised COVID-19 patients with mild disease had higher numbers of expanded clones in both CD4 + and CD8 + subsets (Figure 5K) and the mean clone size was higher within the CD8 + subset (Figure S5L). In keeping with the observation that expanded CD8 T cell clones show increased expression of cytotoxicity markers (Watson et al, 2020a), using a composite gene score for cytotoxicity we found that the number of expanded clones correlated with the average cytotoxicity score across all cells for that individual in both CD4 + T effector (CD4.TEFF/TEFF.prolif) and CD8 + T effector (CD8.TEFF/TEFF.prolif) populations (Figure S5M), and was higher in mild and community COVID-19 cases with reduced cytotoxicity observed in critical and severe disease (Figure 5L).…”
Section: Reduced Diversity In Cd8 + T Cell Populations On Repertoire Analysissupporting
confidence: 79%
“…Cytotoxicity score was calculated using the AddModuleScore function in Seurat (Butler et al, 2018) with a gene-set of the top 50 genes that significantly correlated with IFNG expression in an independent single cell dataset (Watson et al, 2020b) and were identified as variable features in Seurat. The gene-set was then used as an input to generate phenotype scores.…”
Section: Sctcr Cytotoxicity and Kmer Analysismentioning
confidence: 99%
“…High-throughput TCR sequencing has enabled characterization of the repertoire and dynamics of T cell responses with immunotherapy. Recent studies have demonstrated the potential utility of analyzing the clonal composition of blood T cells to predict clinical responses to checkpoint blockade [40,67,88,89]. A correlation has been observed between highly expanded circulating clones and response to therapy in metastatic melanoma patients receiving anti-PD-1 antibody with or without anti-CTLA-4 antibody [40,88].…”
Section: Clinician's Cornermentioning
confidence: 99%
“…Recent studies have demonstrated the potential utility of analyzing the clonal composition of blood T cells to predict clinical responses to checkpoint blockade [40,67,88,89]. A correlation has been observed between highly expanded circulating clones and response to therapy in metastatic melanoma patients receiving anti-PD-1 antibody with or without anti-CTLA-4 antibody [40,88]. Of note, expanded clones at baseline and on-treatment were correlated with a 6-month positive clinical response, highlighting the potential importance of both the pre-existing immune response and early on-treatment dynamics.…”
Section: Clinician's Cornermentioning
confidence: 99%