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posted on 2023-03-30, 23:49 authored by Marie Boutet, Ludiane Gauthier, Marine Leclerc, Gwendoline Gros, Vincent de Montpreville, Nathalie Théret, Emmanuel Donnadieu, Fathia Mami-Chouaib Effects of chemokines and TGF-B on T-cell adhesion to recombinant molecules and specific tumor cells (S1); Influence of TGF-B and chemokines on integrin expression and T-cell motility (S2); Tumor slice staining, influence of anti-CD103 on calcium response and ILK phosphorylation and effect of TGF-B and chemical inhibitors on ILK expression and T-cell adhesion (S3); Influence of siRNA-E-cadherin, shRNA-ILK and rTGF-B on CD103, phospho-ILK and TGFBRI polarization (S4); Effects of TGF-B and chemical inhibitors on granzyme B polarization or redirected target cell lysis (S5).
Funding
INSERM, Association pour la Recherche sur le Cancer (ARC), Institut National du Cancer (INCa), and Ligue contre le Cancer. Cancéropôle IDF and Gustave Roussy
History
ARTICLE 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.
