TY - JOUR
T1 - IL1R1+ cancer-associated fibroblasts drive tumor development and immunosuppression in colorectal cancer
AU - Koncina, E.
AU - Nurmik, M.
AU - Pozdeev, V. I.
AU - Gilson, C.
AU - Tsenkova, M.
AU - Begaj, R.
AU - Stang, S.
AU - Gaigneaux, A.
AU - Weindorfer, C.
AU - Rodriguez, F.
AU - Schmoetten, M.
AU - Klein, E.
AU - Karta, J.
AU - Atanasova, V. S.
AU - Grzyb, K.
AU - Ullmann, P.
AU - Halder, R.
AU - Hengstschläger, M.
AU - Graas, J.
AU - Augendre, V.
AU - Karapetyan, Y. E.
AU - Kerger, L.
AU - Zuegel, N.
AU - Skupin, A.
AU - Haan, S.
AU - Meiser, J.
AU - Dolznig, H.
AU - Letellier, E.
N1 - aCKNOWLEDGMENTS
. 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.)].
© 2023. The Author(s).
PY - 2023/7/17
Y1 - 2023/7/17
N2 - 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.
AB - 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.
KW - Humans
KW - Cancer-Associated Fibroblasts/pathology
KW - Colorectal Neoplasms/drug therapy
KW - Fibroblasts/pathology
KW - Immune Tolerance
KW - Immunosuppression Therapy
KW - Tumor Microenvironment
KW - Cell Proliferation
KW - Receptors, Interleukin-1 Type I/genetics
UR - http://www.scopus.com/inward/record.url?scp=85165029123&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37460545
U2 - 10.1038/s41467-023-39953-w
DO - 10.1038/s41467-023-39953-w
M3 - Article
C2 - 37460545
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4251
ER -