IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer

E. Koncina, M. Nurmik, V. I. Pozdeev, C. Gilson, M. Tsenkova, R. Begaj, S. Stang, A. Gaigneaux, C. Weindorfer, F. Rodriguez, M. Schmoetten, E. Klein, J. Karta, V. S. Atanasova, K. Grzyb, P. Ullmann, R. Halder, M. Hengstschläger, J. Graas, V. AugendreY. E. Karapetyan, L. Kerger, N. Zuegel, A. Skupin, S. Haan, J. Meiser, H. Dolznig, E. Letellier*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

Fibroblasts have a considerable functional and molecular heterogeneity and can play various roles in the tumor microenvironment. Here we identify a pro-tumorigenic IL1R1+, IL-1-high-signaling subtype of fibroblasts, using multiple colorectal cancer (CRC) patient single cell sequencing datasets. This subtype of fibroblasts is linked to T cell and macrophage suppression and leads to increased cancer cell growth in 3D co-culture assays. Furthermore, both a fibroblast-specific IL1R1 knockout and IL-1 receptor antagonist Anakinra administration reduce tumor growth in vivo. This is accompanied by reduced intratumoral Th17 cell infiltration. Accordingly, CRC patients who present with IL1R1-expressing cancer-associated-fibroblasts (CAFs), also display elevated levels of immune exhaustion markers, as well as an increased Th17 score and an overall worse survival. Altogether, this study underlines the therapeutic value of targeting IL1R1-expressing CAFs in the context of CRC.

Original languageEnglish
Article number4251
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 17 Jul 2023

Keywords

  • Humans
  • Cancer-Associated Fibroblasts/pathology
  • Colorectal Neoplasms/drug therapy
  • Fibroblasts/pathology
  • Immune Tolerance
  • Immunosuppression Therapy
  • Tumor Microenvironment
  • Cell Proliferation
  • Receptors, Interleukin-1 Type I/genetics

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