The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
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Fairfax, B.P., Taylor, C.A., Watson, R.A. et al. Nature Medicine volume 26, pages 193–199(2020)
Summary of the findings
We are interested in the inter-individual variation in response to checkpoint immunotherapy for the treatment of metastatic melanoma. Markers of response that are detectable in the periphery have the potential to be clinically relevant as they can be assayed without recourse to biopsy. CD8 T cells show the most pronounced response to checkpoint immunotherapy and we set out to characterise the transcriptomic responses of these cells with treatment, and also determine markers of long-term clinical benefit.
We found that patients with a continued clinical response to therapy at six months had relative upregulation of genes involved in T cell receptor signalling. Using this insight, we categorised patients according to the T cell clonal response 21 days after their first treatment. We found that patients with more separate large peripheral CD8 clones (those >0.5% total repertoire) had a improved long-term outcomes, an observation we replicated in a further cohort. The number of large clones associated with both progression free and overall survival. We proceeded to use single cell sequencing to demonstrate that larger CD8 T cell clones express increased levels of cytotoxic markers and the number of large clones is strongly correlated with CD8 effector cell counts; providing mechanistic insight into our findings.
Going forward we want to assess how clonal size relates with cellular responsive to immunotherapy and deduce other factors involved in this process.
