Distinct spatiotemporal dynamics of CD8+ T cell-derived cytokines in the tumor microenvironment

Mirjam E. Hoekstra, Maarten Slagter, Jos Urbanus, Mireille Toebes, Nadine Slingerland, Iris de Rink, Roelof J.C. Kluin, Marja Nieuwland, Lodewyk F.A. Wessels, More Authors

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Cells in the tumor microenvironment (TME) influence each other through secretion and sensing of soluble mediators, such as cytokines and chemokines. While signaling of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) is integral to anti-tumor immune responses, our understanding of the spatiotemporal behavior of these cytokines is limited. Here, we describe a single cell transcriptome-based approach to infer which signal(s) an individual cell has received. We demonstrate that, contrary to expectations, CD8+ T cell-derived IFNγ is the dominant modifier of the TME relative to TNFα. Furthermore, we demonstrate that cell pools that show abundant IFNγ sensing are characterized by decreased expression of transforming growth factor β (TGFβ)-induced genes, consistent with IFNγ-mediated TME remodeling. Collectively, these data provide evidence that CD8+ T cell-secreted cytokines should be categorized into local and global tissue modifiers, and describe a broadly applicable approach to dissect cytokine and chemokine modulation of the TME.

Original languageEnglish
Pages (from-to)157-167.e9
Number of pages21
JournalCancer Cell
Issue number1
Publication statusPublished - 2024


We thank K. Bresser, A. M. van der Leun, L. Kok and S. Mourragui for input and valuable discussions. We thank staff of the NKI Genomics Core facility for technical support, along with the NKI Research High Performance Computing, Animal Intervention, and Flow Cytometry facilities. This work was supported by a Boehringer Ingelheim Fonds PhD Fellowship (to M.E.H.), ERC AdG SENSIT, grant agreement ID 742259 (to T.N.S.) and institutional funding of the Netherlands Cancer Institute by the Dutch Cancer Society. M.E.H. conceived the study together with M.S. and T.N.S. performed wet lab experiments and wrote the manuscript with M.S. L.F.A.W. and T.N.S. M.S. performed and interpreted bioinformatic analyses. J.U. and M.T. aided in wet lab experiments. N.S. performed exploratory data analysis. R.K. and M.N. designed and performed sequencing experiments and I.d.R. and R.J.C.K. performed data preprocessing. L.F.A.W. and T.N.S. supervised bioinformatic analyses, and T.N.S. supervised wet-lab experiments. All authors have read and approved the manuscript. L.F.A.W. received project funding for unrelated work from Bristoll-Myers-Squibb. T.N.S. is advisor for Allogene Therapeutics, Asher Bio, Merus, Neogene Therapeutics, and Scenic Biotech; is a stockholder in Allogene Therapeutics, Asher Bio, Cell Control, Celsius, Merus, and Scenic Biotech; and is venture partner at Third Rock Ventures, all outside of the current work.


  • cytokine
  • IFN-gamma
  • single cell RNA-seq
  • T cell
  • TNF-alpha
  • tumor microenvironment


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