Cancer immunotherapies specifically target tumors by optimizing the capacity of host cytotoxic T lymphocytes (CTL) to recognize and kill malignant cells. To destroy their target, CTL must migrate to the tumor, infiltrate the stroma and then interact with cancer cells. Recruitment of T lymphocytes within the tumor involves several sequential steps regulated by molecular interactions with a variety of stromal cell types and coordinated by chemotactic agents, extracellular matrix proteins and cell surface adhesion molecules. Integrins are one of the major families of adhesion molecules that contribute to lymphocyte development, migration, extravasation and activation. CD103 integrin and its ligand, the epithelial cell marker E-cadherin, play a crucial role in promoting both tumor cell cytotoxicity and cytokine secretion. Accumulating evidence also indicates that CD103 on CD8+ tumor-infiltrating lymphocytes (TIL) is associated with increased intraepithelial T-cell infiltration and that an enhanced CD103+ TIL subset correlates with improved patient survival in several cancers. However, the contribution of CD103 to promoting T-cell recruitment within epithelial tumor regions, and the influence of TGF-beta, abundant within the tumor microenvironment, on integrin functions and signaling remain poorly understood. In the present study we provide evidence that CD103 is directly involved in T-cell recruitment within epithelial tumor islets and in local early T-cell signaling. Moreover, TGF-beta triggers integrin-mediated functional activities by promoting phosphorylation of integrin-linked kinase (ILK) and its subsequent binding to CD103, thus initiating an “inside-out” signaling leading to activation and clustering of the integrin and thereby initiating an “outside-in” signal that contributes to T-cell stimulation, spreading and cytotoxicity. We conclude that TGF-beta, while known for its protumoral effects, promotes an antitumor CTL response by activating CD103 integrin.
Citation Format: Marie Boutet, Jr., Fathia Mami-Chouaib, Sr. CD103 integrin promotes T-cell recruitment and activation within epithelial tumors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B075.
- ©2016 American Association for Cancer Research.