title: Incorporation of transmembrane hydrophobic mutations in the TCR enhance its surface expression and T cell functional avidity.
abstract: TCR-gene transfer represents an effective way to redirect the specificity of T lymphocytes for therapeutic purposes. Recent successful clinical trials have underscored the potential of this approach in which efficient expression of the exogenous TCR has been directly linked to the efficacy of T cell activity. It has been also demonstrated that the TCR exhibits a lack of stability associated with the presence of positively charged residues in its transmembrane (TM) region. In this study, we designed an original approach selectively to improve exogenous TCR stability by increasing the hydrophobic nature of the TCRα TM region. Incorporation of hydrophobic residues at evolutionarily permissive positions resulted in an enhanced surface expression of the TCR chains, leading to an improved cellular avidity and anti-tumor TCR activity. Furthermore, this strategy was successfully applied to different TCRs, enabling the targeting of human tumors from different histologies. We also show that the combination of these hydrophobic mutations with another TCR-enhancing approach further improved TCR expression and function. Overall, these findings provide information regarding TCR TM composition that can be applied for the improvement of TCR-gene transfer-based treatments.
authors.affiliation: Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.
authors.forename: Astar
authors.initials: A
authors.lastname: Haga-Friedman
authors.forename: Miryam
authors.initials: M
authors.lastname: Horovitz-Fried
authors.forename: Cyrille J
authors.initials: CJ
authors.lastname: Cohen
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D018014:Gene Transfer Techniques; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell