title: NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma.
abstract: Harnessing the immune adjuvant properties of natural killer T (NKT) cells is an effective strategy to generate anticancer immunity. The objective of this study was to increase the potency and durability of vaccine-induced immunity against B cell lymphoma by combining α-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with an agonistic antibody targeting the immune checkpoint molecule 4-1BB (CD137). We observed potent synergy when combining vaccination and anti-4-1BB antibody treatment resulting in significantly enhanced survival of mice harboring Eμ-myc tumors, including complete eradication of lymphoma in over 50% of mice. Tumor-free survival required interferon γ (IFNγ)-dependent expansion of CD8+T cells and was associated with 4-1BB-mediated differentiation of KLRG1+effector CD8+T cells. 'Cured' mice were also resistant to lymphoma re-challenge 80 days later indicating successful generation of immunological memory. Overall, our results demonstrate that therapeutic anticancer vaccination against B cell lymphoma using an NKT cell ligand can be boosted by subsequent co-stimulation through 4-1BB leading to a sustainable immune response that may enhance outcomes to conventional treatment.
authors.affiliation: The University of Queensland Diamantina Institute; The University of Queensland; Translational Research Institute, Brisbane ; Queensland, Australia.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kobayashi
authors.affiliation: The University of Queensland Diamantina Institute; The University of Queensland; Translational Research Institute, Brisbane ; Queensland, Australia.
authors.forename: Brianna L
authors.initials: BL
authors.lastname: Doff
authors.affiliation: The University of Queensland Diamantina Institute; The University of Queensland; Translational Research Institute, Brisbane ; Queensland, Australia.
authors.forename: Rory C
authors.initials: RC
authors.lastname: Rearden
authors.affiliation: The University of Queensland Diamantina Institute; The University of Queensland; Translational Research Institute, Brisbane ; Queensland, Australia.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Leggatt
authors.affiliation: The University of Queensland Diamantina Institute; The University of Queensland; Translational Research Institute, Brisbane ; Queensland, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Mattarollo
keywords: 4–1BB; B cell lymphoma; CRs, complete responses; DPEC, double positive effector cells; EEC, early effector cells; KO, knock-out; MPEC, memory precursor effector cells; NKT cells; SLEC, short-lived effector cells; WT, wild-type.; cIg: isotype control immunoglobulin; cancer vaccine; hematological malignancies; immune checkpoint molecule; immunotherapy; mAb, monoclonal antibody; monoclonal antibody; α-GalCer, α-galactosylceramide; α-galactosylceramide