Abstract 1947P
Background
Immune checkpoint blockers (ICB) have markedly improved survival in patients with metastatic melanoma (MM). However, clinical response remains highly variable and peripheral biomarkers are lacking. CD8+ T cells are a key cellular subset mediating the effect of ICB and previous work has demonstrated that the presence of large CD8+ T cell clones in the peripheral blood (>0.5% of the total repertoire) is associated with positive clinical outcomes. We sought to further characterise and explore the clonal characteristics of the peripheral CD8+ T cell response to ICB at a single-cell level.
Methods
Single cell transcriptome and V(D)J sequencing was performed on CD8+ T cells isolated from the peripheral blood of patients undergoing ICB treatment for MM (n=8) at baseline and 21 days post-treatment. Dimensionality reduction and trajectory inference were subsequently employed to identify and understand the effects of treatment on cellular subpopulations.
Results
We identified 7 subsets of CD8+ T cells, defined by distinctive phenotypes. ICB had a heterogenous effect across these subsets, with the greatest and most unique gene expression changes in the effector and effector memory subsets. Such changes were more marked in larger (>0.5% of repertoire) than smaller clones. By grouping cells based on clonal size, we identify that the effects of ICB vary as a function of clonal size, with clones between 0.5-1% of the repertoire having quantitatively fewer, but qualitatively more relevant, gene expression changes than either hyper-expanded (>2%) or small (<0.1%) clones. Further, ICB had a differential effect on clones that expand following treatment, than those that contract, with expanding clones having both a greater magnitude and qualitatively more relevant gene expression changes than contracting clones. Taken together, we describe a discrete subset of cells which uniquely respond to ICB.
Conclusions
We identify that all cells are not equally affected by ICB, but a subset defined by clonal size and clonal behaviour demonstrate a marked and distinctive response, potentially representing a key cellular target of therapy. This work will aid the search for a prognostic biomarker and further advances understanding of the molecular mechanisms of ICB.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The Wellcome Trust; Cancer Research UK; National Institute for Health Research; Biomedical Research Council.
Disclosure
All authors have declared no conflicts of interest.