Cancer Immunol Res. 2020 Jul 14;canimm.0074.2020. doi: 10.1158/2326-6066.CIR-20-0074. Online ahead of print.
Caroline Spenlé 1 , Thomas Loustau 1 , Devadarssen Murdamoothoo 2 , William Erne 1 , Stéphanie Beghelli-de la Forest Divonne 3 , Romain Veber 4 , Luciana Petti 5 , Pierre Bourdely 6 , Matthias Mörgelin 7 , Eva Maria Brauchle 8 , Gérard Crémel 9 , Vony Randrianarisoa 10 , Abdouramane Camara 11 , Samah Rekima 12 , Sebastian Schaub 13 , Kelly Nouhen 12 , Thomas Imhof 14 , Uwe Hansen 15 , Nicodème Paul 16 , Raphael Carapito 17 , Nicolas Pythoud 18 , Aurelie Hirschler 19 , Christine Carapito 20 , Hélène Dumortier 21 , Christopher G Mueller 22 , Manuel Koch 23 , Katja Schenke-Layland 24 , Shigeyuki Kon 25 , Anne Sudaka 26 , Fabienne Anjuere 27 , Ellen Van Obberghen-Schilling 12 , Gertraud Orend 28
Affiliations
1 U1109 – MN3T, INSERM.
2 U1109, INSERM.
3 CNRS UMR7277 – Inserm U1091 – UNS, Institut de Biologie Valrose (iBV).
4 CNRS 3572 Immunologie, Immunopathologie et Chimie Thérapeutique – I2CT, Institut de Biologie Moléculaire et Cellulaire.
5 CNRS, IPMC, Université Côte d’Azur.
6 IPMC UMR 7275, French National Centre for Scientific Research.
7 Colzyx AB.
8 Dept. of Women’s Health, Research Institute of Women’s Health, Eberhard Karls University Tübingen.
9 U1109 – MN3T lab, INSERM – University of Strasbourg.
10 U1109 – MN3T, Tumor Microenvironment Group, INSERM.
11 CNRS UPR 3572 Immunologie, Immunopathologie et Chimie Thérapeutique – I2CT, Institut de Biologie Moléculaire et Cellulaire.
12 CNRS UMR7277 – INSERM U1091 – UCA, Institut de Biologie Valrose (iBV).
13 CNRS UMR7009 – Sorbonne University, Laboratoire de Biologie du Developpement de Villefranche.
14 Center for Biochemistry, Institute for Dental Research and Oral, Musculoskeletal Research, University of Cologne.
15 Institute for Musculoskeletal Medicine (IMM), University Hospital Muenster.
16 Médecine, Laboratoire d’ImmunoRhumatologie Moléculaire.
17 Laboratoire d’ImmunoRhumatologie Moléculaire.
18 IPHC, DSA, LSMBO, University of Strasbourg.
19 IPHC, University of Strasbourg.
20 Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC, Université de Strasbourg, CNRS.
21 UPR 3572 Immunologie, Immunopathologie et Chimie Thérapeutique – I2CT, CNRS, Institut de Biologie Moléculaire et Cellulaire.
22 University of Strasbourg, CNRS 3572 Immunologie, Immunopathologie et Chimie Thérapeutique.
23 University of Freiburg.
24 Dept. of Women’s Health, Research Institute of Women’s Health, Eberhard Karls University Tuebingen.
25 Faculty of Pharmaceutical Sciences, Fukuyama University.
26 pathology, cal.
27 CNRS UMR7275, Institut de Pharmacologie Moleculaire et Cellulaire.
28 U1109 – MN3T, Tumor Microenvironment Group, INSERM gertraud.orend@inserm.fr.
Abstract
Inherent immune suppression represents a major challenge in the treatment of human cancer. The extracellular matrix molecule tenascin-C promotes cancer by multiple mechanisms, yet the roles of tenascin-C in tumor immunity are incompletely understood. Using a 4NQO-induced oral squamous cell carcinoma (OSCC) model with abundant and absent tenascin-C, we demonstrated that tenascin-C enforced an immune suppressive lymphoid stroma via CCL21/CCR7 signaling, leading to increased metastatic tumors. Through TLR4, tenascin-C increased expression of CCR7 in CD11c+ myeloid cells. By inducing CCL21 in lymphatic endothelial cells via integrin α9β1 and binding to CCL21, tenascin-C immobilized CD11c+ cells in the stroma. Inversion of the lymph node-to-tumor CCL21 gradient, recruitment of T regulatory cells, high expression of anti-inflammatory cytokines and matrisomal components were hallmarks of the tenascin-C-instructed lymphoid stroma. Ablation of tenascin-C or CCR7 blockade inhibited the lymphoid immune suppressive stromal properties, reducing tumor growth, progression and metastasis. Thus, targeting CCR7 could be relevant in human head and neck tumors as high tenascin-C expression and an immune suppressive stroma correlate to poor patient survival.
PMID: 32665262
DOI: 10.1158/2326-6066.CIR-20-0074