Immune checkpoint therapy responders display early clonal expansion of tumor infiltrating lymphocytes

Joel Kidman, Rachael M. Zemek, John William Sidhom, Debora Correa, Nicola Principe, Fezaan Sheikh, Vanessa S. Fear, Catherine A. Forbes, Abha Chopra, Louis Boon, Ayham Zaitouny, Emma de Jong, Robert A. Holt, Matt Jones, Michael J. Millward, Timo Lassmann, Alistair R.R. Forrest, Anna K. Nowak, Mark Watson, Richard A. LakeW. Joost Lesterhuis, Jonathan Chee

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Immune checkpoint therapy (ICT) causes durable tumour responses in a subgroup of patients, but it is not well known how T cell receptor beta (TCRβ) repertoire dynamics contribute to the therapeutic response. Using murine models that exclude variation in host genetics, environmental factors and tumour mutation burden, limiting variation between animals to naturally diverse TCRβ repertoires, we applied TCRseq, single cell RNAseq and flow cytometry to study TCRβ repertoire dynamics in ICT responders and non-responders. Increased oligoclonal expansion of TCRβ clonotypes was observed in responding tumours. Machine learning identified TCRβ CDR3 signatures unique to each tumour model, and signatures associated with ICT response at various timepoints before or during ICT. Clonally expanded CD8+ T cells in responding tumours post ICT displayed effector T cell gene signatures and phenotype. An early burst of clonal expansion during ICT is associated with response, and we report unique dynamics in TCRβ signatures associated with ICT response.

Original languageEnglish
Article number2345859
JournalOncoImmunology
Volume13
Issue number1
DOIs
Publication statusPublished - 2024

Keywords

  • Immune checkpoint therapy
  • immune repertoire
  • machine learning
  • T cell receptor (TCR) sequencing
  • T cells
  • tumour-infiltrating lymphocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

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