IL1R1 protein, human; Receptors, Interleukin-1 Type I; Humans; Fibroblasts/pathology; Immune Tolerance; Immunosuppression Therapy; Tumor Microenvironment; Cell Proliferation; Receptors, Interleukin-1 Type I/genetics; Cancer-Associated Fibroblasts/pathology; Colorectal Neoplasms/drug therapy; Colorectal Neoplasms/genetics; Cancer-Associated Fibroblasts; Colorectal Neoplasms; Fibroblasts; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
KONCINA, Eric ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
NURMIK, Martin ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Serge HAAN
POZDEEV, Vitaly ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
GILSON, Cédric ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
TSENKOVA, Mina ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
BEGAJ, Rubens ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
Stang, S; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
GAIGNEAUX, Anthoula ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Weindorfer, C; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
RODRIGUEZ, Fabien ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
SCHMOETTEN, Maryse ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
KLEIN, Eliane ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
KARTA, Jessica ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine > Team Elisabeth LETELLIER
Atanasova, V S; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
ULLMANN, Pit ; University of Luxembourg > Faculty of Science, Technology and Medicine > Department of Life Sciences and Medicine
HALDER, Rashi ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Sequencing Platform
Hengstschläger, M; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria
Graas, J; Clinical and Epidemiological Investigation Center, Department of Population Health, Luxembourg Institute of Health, Luxembourg, Luxembourg
Augendre, V; National Center of Pathology, Laboratoire National de Santé, Dudelange, Luxembourg
Karapetyan, Y E; Integrated BioBank of Luxembourg, Dudelange, Luxembourg
KERGER, Lucien ; University of Luxembourg ; Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
Zuegel, N; Department of Surgery, Centre Hospitalier Emile Mayrisch, Esch-sur-Alzette, Luxembourg
SKUPIN, Alexander ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Integrative Cell Signalling
HAAN, Serge ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
MEISER, Johannes ; University of Luxembourg ; Cancer Metabolism Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg
Dolznig, H ; Center for Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria. helmut.dolznig@meduniwien.ac.at
LETELLIER, Elisabeth ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
We thank the patients who kindly donated their samples and made this study possible. We thank all the contributing surgeons and nurses from the Centre Hospitalier Emile Mayrisch, the Laboratoire National de Santé and the Clinical and Epidemiological Investigation Centre of the LIH for their work with the patients. We would like to thank the Fondation Cancer for its support during the setup of the Luxembourgish CRC patient cohort. We also thank Prof. Dr. Michel Mittelbronn and the pathologists and macroscopy team from NCP/LNS. The authors would also like to thank their collaborators at the IBBL, Dr. Fay Betsou, Dr. Nikolai Goncharenko, Dr. Christelle Bahlawane and Amélie Gaignaux for the overall setup of the patient sample collection and the management of the cohort. We would also like to thank Dr. Lynn Bonetti for providing us with the Th17 gene signature. We would also like to thank the whole team of the animal facility at the University of Luxembourg, especially our veterinarian Jennifer Behm and our facility manager Djalil Coowar. Finally we would like to thank Professor Olivier de Wever for the kind gift of the Ct5.3 fibroblasts. Parts of the data processing presented in this manuscript were carried out using the HPC facility of the University of Luxembourg ( https://hpc.uni.lu ). Figures a, and Supplementary Fig. were created with BioRender.com ( https://biorender.com ). The diagrams shown in Figs. b, and Supplementary Fig. were generated using Inkscape ( https://inkscape.org/ ) and the mouse clipart used in Figs. b and are adapted from “Mouse” from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License ( https://smart.servier.com )’. This work was supported by the Luxembourg National Research Fund [CORE/C16/BM/11282028 (L.E.), CORE/C20/BM/14591557 (L.E.), PoC/18/12554295 (L.E.), PRIDE Doctoral Research in the scope of the Doctoral Teaching Unit—CANBIO (PRIDE15/10675146/CANBIO) to N.M. and B.R. and MICROH PRIDE17/11823097 to T.M., as well as by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (E-AGR-0023-10-Z; T.M.), the Fondation Schumacher (B.R.), and the Fondation Gustave et Simone Prévot (L.E.). The project was further supported by CCC research grant (Initiative Krebsforschung) of the MedUni Vienna (D.H.), European Commission, SECRET ITN 859962 (D.H.) and Gesellschaft für Forschungsförderung Niederösterreich m.b.H.; LSC18-017 (D.H.)]. The collection of colorectal cancer samples is supported by the Fondation Cancer (L.E.) and the Doctoral School in Science and Engineering (T.M.) and the Department of Life Sciences and Medicine at the University of Luxembourg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.We thank the patients who kindly donated their samples and made this study possible. We thank all the contributing surgeons and nurses from the Centre Hospitalier Emile Mayrisch, the Laboratoire National de Santé and the Clinical and Epidemiological Investigation Centre of the LIH for their work with the patients. We would like to thank the Fondation Cancer for its support during the setup of the Luxembourgish CRC patient cohort. We also thank Prof. Dr. Michel Mittelbronn and the pathologists and macroscopy team from NCP/LNS. The authors would also like to thank their collaborators at the IBBL, Dr. Fay Betsou, Dr. Nikolai Goncharenko, Dr. Christelle Bahlawane and Amélie Gaignaux for the overall setup of the patient sample collection and the management of the cohort. We would also like to thank Dr. Lynn Bonetti for providing us with the Th17 gene signature. We would also like to thank the whole team of the animal facility at the University of Luxembourg, especially our veterinarian Jennifer Behm and our facility manager Djalil Coowar. Finally we would like to thank Professor Olivier de Wever for the kind gift of the Ct5.3 fibroblasts. Parts of the data processing presented in this manuscript were carried out using the HPC facility of the University of Luxembourg61(https://hpc.uni.lu). Figures 4 a, 7 and Supplementary Fig. 4a were created with BioRender.com (https://biorender.com). The diagrams shown in Figs. 5 b, 6a and Supplementary Fig. 1b were generated using Inkscape (https://inkscape.org/) and the mouse clipart used in Figs. 5 b and 6a are adapted from “Mouse” from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License (https://smart.servier.com)’. This work was supported by the Luxembourg National Research Fund [CORE/C16/BM/11282028 (L.E.), CORE/C20/BM/14591557 (L.E.), PoC/18/12554295 (L.E.), PRIDE Doctoral Research in the scope of the Doctoral Teaching Unit—CANBIO (PRIDE15/10675146/CANBIO) to N.M. and B.R. and MICROH PRIDE17/11823097 to T.M., as well as by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (E-AGR-0023-10-Z; T.M.), the Fondation Schumacher (B.R.), and the Fondation Gustave et Simone Prévot (L.E.). The project was further supported by CCC research grant (Initiative Krebsforschung) of the MedUni Vienna (D.H.), European Commission, SECRET ITN 859962 (D.H.) and Gesellschaft für Forschungsförderung Niederösterreich m.b.H.; LSC18-017 (D.H.)]. The collection of colorectal cancer samples is supported by the Fondation Cancer (L.E.) and the Doctoral School in Science and Engineering (T.M.) and the Department of Life Sciences and Medicine at the University of Luxembourg. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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