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Research Articles

Tenascin-C Orchestrates an Immune-Suppressive Tumor Microenvironment in Oral Squamous Cell Carcinoma

Caroline Spenlé, Thomas Loustau, Devadarssen Murdamoothoo, William Erne, Stephanie Beghelli-de la Forest Divonne, Romain Veber, Luciana Petti, Pierre Bourdely, Matthias Mörgelin, Eva-Maria Brauchle, Gérard Cremel, Vony Randrianarisoa, Abdouramane Camara, Samah Rekima, Sebastian Schaub, Kelly Nouhen, Thomas Imhof, Uwe Hansen, Nicodème Paul, Raphael Carapito, Nicolas Pythoud, Aurélie Hirschler, Christine Carapito, Hélène Dumortier, Christopher G. Mueller, Manuel Koch, Katja Schenke-Layland, Shigeyuki Kon, Anne Sudaka, Fabienne Anjuère, Ellen Van Obberghen-Schilling and Gertraud Orend
Caroline Spenlé
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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  • ORCID record for Caroline Spenlé
Thomas Loustau
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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Devadarssen Murdamoothoo
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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William Erne
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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Stephanie Beghelli-de la Forest Divonne
2Université Côte d'Azur, CNRS, INSERM, iBV, Nice, France.
3Centre Antoine Lacassagne, Nice, France.
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Romain Veber
4Institut de Biologie Moléculaire et Cellulaire, CNRS, UPR3572 Immunologie, Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
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Luciana Petti
5Université Côte d'Azur, CNRS, IPMC, Valbonne-Sophia Antipolis, France.
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Pierre Bourdely
5Université Côte d'Azur, CNRS, IPMC, Valbonne-Sophia Antipolis, France.
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Matthias Mörgelin
6Colzyx AB, Lund, Sweden.
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Eva-Maria Brauchle
7Department of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany.
8The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany.
9Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies,” Eberhard Karls University Tübingen, Tübingen, Germany.
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Gérard Cremel
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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  • ORCID record for Gérard Cremel
Vony Randrianarisoa
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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Abdouramane Camara
4Institut de Biologie Moléculaire et Cellulaire, CNRS, UPR3572 Immunologie, Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
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Samah Rekima
2Université Côte d'Azur, CNRS, INSERM, iBV, Nice, France.
3Centre Antoine Lacassagne, Nice, France.
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Sebastian Schaub
2Université Côte d'Azur, CNRS, INSERM, iBV, Nice, France.
3Centre Antoine Lacassagne, Nice, France.
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Kelly Nouhen
5Université Côte d'Azur, CNRS, IPMC, Valbonne-Sophia Antipolis, France.
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Thomas Imhof
10Institute for Dental Research and Oral, Musculoskeletal Research, Center for Biochemistry, University of Cologne, Cologne, Germany.
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Uwe Hansen
11Institute for Musculoskeletal Medicine (IMM), University Hospital Muenster, Muenster, Germany.
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Nicodème Paul
12INSERM U1109, GENOMAX, Strasbourg, France.
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Raphael Carapito
12INSERM U1109, GENOMAX, Strasbourg, France.
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Nicolas Pythoud
13IPHC, Cronenbourg, France.
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Aurélie Hirschler
13IPHC, Cronenbourg, France.
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Christine Carapito
13IPHC, Cronenbourg, France.
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Hélène Dumortier
4Institut de Biologie Moléculaire et Cellulaire, CNRS, UPR3572 Immunologie, Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
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Christopher G. Mueller
4Institut de Biologie Moléculaire et Cellulaire, CNRS, UPR3572 Immunologie, Immunopathologie et Chimie Thérapeutique, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
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Manuel Koch
10Institute for Dental Research and Oral, Musculoskeletal Research, Center for Biochemistry, University of Cologne, Cologne, Germany.
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Katja Schenke-Layland
7Department of Women's Health, Research Institute of Women's Health, Eberhard Karls University Tübingen, Tübingen, Germany.
8The Natural and Medical Sciences Institute (NMI) at the University of Tübingen, Reutlingen, Germany.
9Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies,” Eberhard Karls University Tübingen, Tübingen, Germany.
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Shigeyuki Kon
14Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
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Anne Sudaka
2Université Côte d'Azur, CNRS, INSERM, iBV, Nice, France.
3Centre Antoine Lacassagne, Nice, France.
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Fabienne Anjuère
5Université Côte d'Azur, CNRS, IPMC, Valbonne-Sophia Antipolis, France.
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Ellen Van Obberghen-Schilling
2Université Côte d'Azur, CNRS, INSERM, iBV, Nice, France.
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  • ORCID record for Ellen Van Obberghen-Schilling
  • For correspondence: gertraud.orend@inserm.fr Ellen.VAN-OBBERGHEN@unice.fr
Gertraud Orend
1Université Strasbourg, INSERM U1109-MN3T, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, and The Tumor Microenvironment Laboratory, Hopital Civil, Institut d'Hématologie et d'Immunologie, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
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  • For correspondence: gertraud.orend@inserm.fr Ellen.VAN-OBBERGHEN@unice.fr
DOI: 10.1158/2326-6066.CIR-20-0074 Published September 2020
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:1122–38

  • Received January 25, 2020.
  • Revision received April 19, 2020.
  • Accepted July 1, 2020.
  • Published first July 14, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (9)
September 2020
Volume 8, Issue 9
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Tenascin-C Orchestrates an Immune-Suppressive Tumor Microenvironment in Oral Squamous Cell Carcinoma
Caroline Spenlé, Thomas Loustau, Devadarssen Murdamoothoo, William Erne, Stephanie Beghelli-de la Forest Divonne, Romain Veber, Luciana Petti, Pierre Bourdely, Matthias Mörgelin, Eva-Maria Brauchle, Gérard Cremel, Vony Randrianarisoa, Abdouramane Camara, Samah Rekima, Sebastian Schaub, Kelly Nouhen, Thomas Imhof, Uwe Hansen, Nicodème Paul, Raphael Carapito, Nicolas Pythoud, Aurélie Hirschler, Christine Carapito, Hélène Dumortier, Christopher G. Mueller, Manuel Koch, Katja Schenke-Layland, Shigeyuki Kon, Anne Sudaka, Fabienne Anjuère, Ellen Van Obberghen-Schilling and Gertraud Orend
Cancer Immunol Res September 1 2020 (8) (9) 1122-1138; DOI: 10.1158/2326-6066.CIR-20-0074

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Tenascin-C Orchestrates an Immune-Suppressive Tumor Microenvironment in Oral Squamous Cell Carcinoma
Caroline Spenlé, Thomas Loustau, Devadarssen Murdamoothoo, William Erne, Stephanie Beghelli-de la Forest Divonne, Romain Veber, Luciana Petti, Pierre Bourdely, Matthias Mörgelin, Eva-Maria Brauchle, Gérard Cremel, Vony Randrianarisoa, Abdouramane Camara, Samah Rekima, Sebastian Schaub, Kelly Nouhen, Thomas Imhof, Uwe Hansen, Nicodème Paul, Raphael Carapito, Nicolas Pythoud, Aurélie Hirschler, Christine Carapito, Hélène Dumortier, Christopher G. Mueller, Manuel Koch, Katja Schenke-Layland, Shigeyuki Kon, Anne Sudaka, Fabienne Anjuère, Ellen Van Obberghen-Schilling and Gertraud Orend
Cancer Immunol Res September 1 2020 (8) (9) 1122-1138; DOI: 10.1158/2326-6066.CIR-20-0074
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