Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis.
Various T cell adhesion molecules and their cognate receptors on target cells promote T cell receptor (TCR)-mediated cell killing. In this report, we demonstrate that the interaction of epithelial cell marker E-cadherin with integrin alpha(E)(CD103)beta(7), often expressed by tumor-infiltrating lymphocytes (TILs), plays a major role in effective tumor cell lysis. Indeed, we found that although tumor-specific CD103(+) TIL-derived cytotoxic T lymphocyte (CTL) clones are able to kill E-cadherin(+)/intercellular adhesion molecule 1(-) autologous tumor cells, CD103(-) peripheral blood lymphocyte (PBL)-derived counterparts are inefficient. This cell killing is abrogated after treatment of the TIL clones with a blocking anti-CD103 monoclonal antibody or after targeting E-cadherin in the tumor using ribonucleic acid interference. Confocal microscopy analysis also demonstrated that alpha(E)beta(7) is recruited at the immunological synapse and that its interaction with E-cadherin is required for cytolytic granule polarization and subsequent exocytosis. Moreover, we report that the CD103(-) profile, frequently observed in PBL-derived CTL clones and associated with poor cytotoxicity against the cognate tumor, is up-regulated upon TCR engagement and transforming growth factor beta1 treatment, resulting in strong potentiation of antitumor lytic function. Thus, CD8(+)/CD103(+) tumor-reactive T lymphocytes infiltrating epithelial tumors most likely play a major role in antitumor cytotoxic response through alpha(E)beta(7)-E-cadherin interactions.
Le Floc'h
Audrey
A
Institut National de la Santé et de la Recherche Médicale (INSERM) U753 and 2Unité de génomique fonctionnelle, Institut Fédératif de Recherche (IFR)-54, Institut Gustave Roussy, Villejuif Cedex 94805, France.
Jalil
Abdelali
A
Vergnon
Isabelle
I
Le Maux Chansac
Béatrice
B
Lazar
Vladimir
V
Bismuth
Georges
G
Chouaib
Salem
S
Mami-Chouaib
Fathia
F
D015820:Cadherins / Q000378:metabolism / Q000502:physiology*; D018287:Carcinoma, Large Cell / Q000276:immunology / Q000517:prevention & control; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000276:immunology*; D003594:Cytoplasmic Granules / Q000276:immunology* / Q000378:metabolism; D005089:Exocytosis / Q000276:immunology*; D006801:Humans; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D015820:Cadherins; D016023:Integrins; C070709:integrin alphaEbeta7