Using multiple CRC patient scRNAseq datasets, Koncina, Nurmik, and Pozdeev et al. identified a pro-tumorigenic CAF subtype with elevated IL1R1 expression and increased IL-1β-signaling, correlating with an immunosuppressive TME and low overall survival in patients with the CMS4 CRC subtype. IL-1β-stimulated CAFs secreted pro-inflammatory cytokines, induced macrophage polarization towards a pro-tumorigenic (M2-like) phenotype, and increased T cell exhaustion. Fibroblast-specific IL1R1 knockout or IL-1 receptor inhibition decreased pro-tumorigenic Th17 infiltration and immunosuppression in the TME, and reduced tumor growth in CRC xenograft models.
Contributed by Shishir Pant
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.
Author Info: (1) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (2) Molecular Disease Mechanisms Group, Department o
Author Info: (1) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (2) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (3) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (4) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (5) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (6) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (7) Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. (8) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (9) Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. (10) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (11) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (12) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (13) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (14) Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. (15) Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg. (16) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (17) Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg. (18) Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. (19) Clinical and Epidemiological Investigation Center, Department of Population Health, Luxembourg Institute of Health, Luxembourg, Luxembourg. (20) National Center of Pathology, Laboratoire National de Sant, Dudelange, Luxembourg. (21) Integrated BioBank of Luxembourg, Dudelange, Luxembourg. (22) Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg. (23) Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg. (24) Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg. (25) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. (26) Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg. (27) Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. helmut.dolznig@meduniwien.ac.at. (28) Molecular Disease Mechanisms Group, Department of Life Sciences and Medicine, University of Luxembourg, Belval, Luxembourg. elisabeth.letellier@uni.lu.
