RESUMO
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.
Assuntos
Fibroblastos Associados a Câncer , Neoplasias Colorretais , Humanos , Fibroblastos Associados a Câncer/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Fibroblastos/patologia , Tolerância Imunológica , Terapia de Imunossupressão , Microambiente Tumoral , Proliferação de Células , Receptores Tipo I de Interleucina-1/genéticaRESUMO
Complete chemical selectivity (i.e., chemospecificity) has been achieved in the homogeneous deuteration of C5-C6 and endocyclic C10-C11 prostaglandin double bonds without arrangement or partial reduction of C13-C14- or C8-C12 double bonds. The homogeneous deuteration reaction utilizes protection of the C13-C14 double bond as the C15O-silyl ether and protection of the carboxyl group as the methyl ester prior to reduction under molecular deuterium with tris(triphenylphosphine)chlorohodium (I) (Wilkinson's catalyst) in 60:40 acetone:benzene at 25 degrees C. The reaction has been used to prepare six specifically deuterated prostaglandin: 5,6-dideuterio-PGE1 alpha 5,6-dideuterio-PGE1, 5,6-dideuterio-PGB1, 3,3,4,4,5,6-hexadeuterio-PGF1 alpha, 5,6,10,11-tetradeuterio-11-deoxy-PGE1, and 10, 11-dideuterio-11-deoxy-PGE1.