title: γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs.
abstract: Immunotherapy with innate immune cells has recently evoked broad interest as a novel treatment option for cancer patients. γ9δ2T cells in particular are emerging as an innate cell population with high frequency and strong antitumor reactivity, which makes them and their receptors promising candidates for immune interventions. However, clinical trials have so far reported only limited tumor control by adoptively transferred γ9δ2T cells. As a potential explanation for this lack of efficacy, we found unexpectedly high variability in tumor recognition within the physiologic human γ9δ2T-cell repertoire, which is substantially regulated by the CDR3 domains of individual γ9δ2TCRs. In the present study, we demonstrate that the reported molecular requirements of CDR3 domains to interact with target cells shape the physiologic γ9δ2T-cell repertoire and, most likely, limit the protective and therapeutic antitumor efficacy of γ9δ2T cells. Based on these findings, we propose combinatorial-γδTCR-chain exchange as an efficient method for designing high-affinity γ9δ2TCRs that mediate improved antitumor responses when expressed in αβT cells both in vitro and in vivo in a humanized mouse model.
authors.affiliation: Departments of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Cordula
authors.initials: C
authors.lastname: Gründer
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Dorp
authors.forename: Samantha
authors.initials: S
authors.lastname: Hol
authors.forename: Esther
authors.initials: E
authors.lastname: Drent
authors.forename: Trudy
authors.initials: T
authors.lastname: Straetemans
authors.forename: Sabine
authors.initials: S
authors.lastname: Heijhuurs
authors.forename: Kirsten
authors.initials: K
authors.lastname: Scholten
authors.forename: Wouter
authors.initials: W
authors.lastname: Scheper
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sebestyen
authors.forename: Anton
authors.initials: A
authors.lastname: Martens
authors.forename: Roland
authors.initials: R
authors.lastname: Strong
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kuball
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000502:physiology; D019675:Genes, T-Cell Receptor gamma / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016219:Immunotherapy, Adoptive / Q000379:methods; D020014:K562 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary / Q000502:physiology; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018984:Epitopes, T-Lymphocyte; D007142:Immunoglobulin gamma-Chains