title: TGFβ Signaling Intersects with CD103 Integrin Signaling to Promote T-Lymphocyte Accumulation and Antitumor Activity in the Lung Tumor Microenvironment.
abstract: Homing of CD8(+) T lymphocytes to the tumor microenvironment is an important step for mounting a robust antitumor immune response. TGFβ is responsible for CD103 (αEβ7) integrin induction in activated intraepithelial CD8(+) T lymphocytes. However, the interplay between TGFβ and CD103 and their contribution to T-cell infiltration and antitumor activity remain unknown. Here, we used viable human lung tumor slices and autologous tumor antigen-specific T-lymphocyte clones to provide evidence that CD103 is directly involved in T-lymphocyte recruitment within epithelial tumor islets and intratumoral early T-cell signaling. Moreover, TGFβ enhanced CD103-dependent T-cell adhesion and signaling, whereas it inhibited leukocyte function-associated antigen (LFA)-1 (αLβ2) integrin expression and LFA-1-mediated T-lymphocyte functions. Mechanistic investigations revealed that TGFβ bound to its receptors (TGFBR), which promoted the recruitment and phosphorylation of integrin-linked kinase (ILK) by TGFBR1. We further show that ILK interacted with the CD103 intracellular domain, resulting in protein kinase B (PKB)/AKT activation, thereby initiating integrin inside-out signaling. Collectively, our findings suggest that the abundance of TGFβ in the tumor microenvironment may in fact engage with integrin signaling pathways to promote T-lymphocyte antitumor functions, with potential implications for T-cell-based immunotherapies for cancer. Cancer Res; 76(7); 1757-69. ©2016 AACR.
authors.affiliation: INSERM (Institut National de la Santé et de la Recherche Médicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, France. INSERM, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Boutet
authors.affiliation: INSERM (Institut National de la Santé et de la Recherche Médicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, France. INSERM, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Ludiane
authors.initials: L
authors.lastname: Gauthier
authors.affiliation: INSERM (Institut National de la Santé et de la Recherche Médicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, France. INSERM, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Leclerc
authors.affiliation: INSERM (Institut National de la Santé et de la Recherche Médicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, France. INSERM, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Gros
authors.affiliation: INSERM (Institut National de la Santé et de la Recherche Médicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, France. Centre Chirurgical Marie-Lannelongue, Service d'Anatomie Pathologique, LePlessis-Robinson, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: de Montpreville
authors.affiliation: INSERM UMR1085, IRSET, Université de Rennes 1, Rennes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Théret
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France. CNRS (Centre National de la Recherche Scientifique) UMR8104, Paris, France. Université Paris Descartes, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Donnadieu
authors.affiliation: INSERM (Institut National de la Santé et de la Recherche Médicale) UMR1186, Laboratory Integrative Tumor Immunology and Genetic Oncology, France. INSERM, Gustave Roussy, Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France. fathia.mami-chouaib@gustaveroussy.fr.
authors.forename: Fathia
authors.initials: F
authors.lastname: Mami-Chouaib
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism*; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018613:Microscopy, Confocal; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D015703:Antigens, CD; D017252:CD3 Complex; D039001:Integrin alpha Chains; D016212:Transforming Growth Factor beta; C091367:alpha E integrins