302 - Ex vivo programming of T cell trafficking and retention within tumors by TGF-β

Abstract

Adoptive immunotherapy (AI) is a promising approach that has proved effective across different type of tumors including melanoma and Epstein-Barr virus lymphomas. However, despite recent successes, many patients still fail to respond. One of the major challenges for AI is to be able to generate antigen-specific T cells that are capable to effectively traffic and be retained into the tumor. Thus, the development of strategies that could potentially increase infiltration of T cells into neoplastic microenvironments is critical for the success of AI. Transforming Growth Factor beta (TGF-β) is a pleiotropic cytokine mostly known for its immunosuppressive properties. Paradoxically, it has been recently shown that the abundance of TGF-β in the tumor microenvironment may promote T-lymphocyte recruitment and antitumor functions within epithelial cancers. This may occur through the induction of the integrin CD103 expression that promotes effector T-cell adhesion to tumor cells and also triggers intracellular signaling events that provide co-stimulatory signals. Thus, we hypothesise that TGF-β exposure during ex vivo T cell activation for AI may confer a tumor infiltration/retention phenotype to effector T cell within tumors in vivo and hence improve AI efficacy. Using OT-I TcR transgenic model, we found that exogenous TGF-β favors the expression of the integrin CD103 and the chemokine receptor CXCR3 in ex-vivo stimulated OT1-T cells in the presence of the cognate antigen. We also found that TGF-β-treated T cells exhibited strong migration to recombinant CXCL9, CXCL10 and CXCL11, the three CXCR3 ligands. Furthermore, using in vivo competitive homing assays, we found that TGF-β improves T-cell trafficking in Lewis lung carcinoma expressing OVA peptide (LLC-OVA) tumors. Finally, adoptive transfer of TGF-β-treated T cells into LLC-OVA-bearing mice slightly but significantly delayed tumor growth which correlated with higher intratumoral T cell infiltration and maintenance of CD103 expression in vivo. All together, these data suggest that ex-vivo stimulation of antigen-specific T cells with TGF-β may enhance localization within tumor thereby enhancing the anti-tumor response and improving the therapeutic effectiveness of AI.