title: Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens.
abstract: Cytotoxic T cells recognize, via their T cell receptors (TCRs), small antigenic peptides presented by the major histocompatibility complex (pMHC) on the surface of professional antigen-presenting cells and infected or malignant cells. The efficiency of T cell triggering critically depends on TCR binding to cognate pMHC, i.e., the TCR-pMHC structural avidity. The binding and kinetic attributes of this interaction are key parameters for protective T cell-mediated immunity, with stronger TCR-pMHC interactions conferring superior T cell activation and responsiveness than weaker ones. However, high-avidity TCRs are not always available, particularly among self/tumor antigen-specific T cells, most of which are eliminated by central and peripheral deletion mechanisms. Consequently, systematic assessment of T cell avidity can greatly help distinguishing protective from non-protective T cells. Here, we review novel strategies to assess TCR-pMHC interaction kinetics, enabling the identification of the functionally most-relevant T cells. We also discuss the significance of these technologies in determining which cells within a naturally occurring polyclonal tumor-specific T cell response would offer the best clinical benefit for use in adoptive therapies, with or without T cell engineering.
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV), University of Lausanne , Epalinges , Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Hebeisen
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV), University of Lausanne , Epalinges , Switzerland.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Allard
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV), University of Lausanne , Epalinges , Switzerland.
authors.forename: Philippe O
authors.initials: PO
authors.lastname: Gannon
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne , Epalinges , Switzerland ; TCMetrix Sàrl , Epalinges , Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV), University of Lausanne , Epalinges , Switzerland ; Ludwig Center for Cancer Research, University of Lausanne , Epalinges , Switzerland.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser
authors.affiliation: Department of Oncology, Lausanne University Hospital Center (CHUV), University of Lausanne , Epalinges , Switzerland ; Ludwig Center for Cancer Research, University of Lausanne , Epalinges , Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
keywords: NTAmers; T cell functionality; TCR affinity; TCR structural avidity; cytotoxic T cells; immunotherapy; melanoma; tumor antigens