title: PD-1 expression conditions T cell avidity within an antigen-specific repertoire.
abstract: Despite its negative regulatory role on tumor-specific T cells, Programmed cell death 1 (PD-1) is also a marker of activated tumor-infiltrating T cells. In cancer, PD-1 blockade partially reverses T cell dysfunction allowing the amplification of tumor reactive T cells. Here, we investigated the role of PD-1 signaling on effector/memory human T cells specific for shared melanoma antigens, derived from blood. We documented for the first time the existence of melanoma-specific T cell clones unable to express PD-1. This stable feature was due to the persistent methylation of thePDCD1promoter. These PD-1negclones were of lower avidity than their PD-1poscounterparts, suggesting that high-affinity-specific T cell clones unable to express PD-1 are not or rarely present in peripheral blood, as they are probably eliminated by negative selection, due to their high reactivity. We also documented the existence of such PD-1negT cell clones in melanoma tumor-infiltrating lymphocytes (TIL), which also exhibited a lower functional avidity than PD-1posTIL clones. This clearly shows that PD-1 expression identifies antigen-specific T cell clonotypes of high functional avidity. Finally, we demonstrated that PD-1 blockade during thein vitroselection process of Melan-A-specific T cells favored the amplification of higher avidity T cell clonotypes. This preferential amplification of high-avidity memory T cells upon PD-1 blockade resonates with the expansion of reactive T cells, including neo-antigen-specific T cells observed in anti-PD-1-treated patients. This feature should also be a useful biomarker of clinical efficiency, while providing new insights for adoptive transfer treatments.
authors.affiliation: Inserm UMR892/CNRS UMR6299/Univ Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France; Department of Dermato-cancerology of CHU Nantes, Nantes, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Simon
authors.affiliation: Inserm UMR892/CNRS UMR6299/Univ Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France; Department of Dermato-cancerology of CHU Nantes, Nantes, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Vignard
authors.affiliation: Inserm UMR892/CNRS UMR6299/Univ Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France; Department of Dermato-cancerology of CHU Nantes, Nantes, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Florenceau
authors.affiliation: Inserm UMR892/CNRS UMR6299/Univ Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France; Department of Dermato-cancerology of CHU Nantes, Nantes, France.
authors.forename: B
authors.initials: B
authors.lastname: Dreno
authors.affiliation: Inserm UMR892/CNRS UMR6299/Univ Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France; Department of Dermato-cancerology of CHU Nantes, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Khammari
authors.affiliation: Inserm UMR892/CNRS UMR6299/Univ Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France.
authors.forename: F
authors.initials: F
authors.lastname: Lang
authors.affiliation: Inserm UMR892/CNRS UMR6299/Univ Nantes, Nantes, France; LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France; Department of Dermato-cancerology of CHU Nantes, Nantes, France.
authors.forename: N
authors.initials: N
authors.lastname: Labarriere
keywords: Adoptive T cell transfer; Melan-A; PD-1; T cell avidity; immunotherapy; melanoma