Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis.

Abstract

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.

• Authors: Audrey Le Floc'h, Abdelali Jalil, Isabelle Vergnon, Béatrice Le Maux Chansac, Vladimir Lazar, Georges Bismuth, Salem Chouaib, Fathia Mami-Chouaib
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 204 Issue 3 Pg. 559-70 (Mar 19 2007) ISSN: 0022-1007 [Print] United States
• PMID: 17325197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Integrins
• integrin alphaEbeta7

Topics

• Cadherins (metabolism, physiology)
• Carcinoma, Large Cell (immunology, prevention & control)
• Cell Line, Tumor
• Cell Polarity (immunology)
• Cytoplasmic Granules (immunology, metabolism)
• Exocytosis (immunology)
• Humans
• Integrins (metabolism, physiology)
• Lung Neoplasms (immunology, metabolism, prevention & control)
• T-Lymphocytes, Cytotoxic (immunology, metabolism)