OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum

Tetje C. van der Sluis, Guillaume Beyrend, Esmé T.I. van der Gracht, Tamim Abdelaal, Simon P. Jochems, Robert A. Belderbos, Thomas H. Wesselink, Suzanne van Duikeren, Ramon Arens*, More Authors

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

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Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.

Original languageEnglish
Article number100939
Number of pages26
JournalCell Reports Medicine
Issue number3
Publication statusPublished - 2023


  • immune checkpoint therapy
  • immunotherapy
  • mass cytometry
  • predictive biomarkers
  • single-cell RNA sequencing
  • systemic immune activation
  • T cells


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