title: Control of B-cell lymphoma by therapeutic vaccination and acquisition of immune resistance is independent of direct tumour IFN-gamma signalling.
abstract: Immunomodulatory therapies can effectively control haematological malignancies by promoting antitumour immunity. Previously, we reported transient growth of poorly immunogenic murine non-Hodgkin B-cell lymphomas (B-NHL) by targeting natural killer T (NKT) cells with a therapeutic vaccine approach. Therapeutic efficacy was highly dependent on the ability of the vaccine to provoke rapid interferon-gamma (IFNγ) production from NKT and NK cells. By manipulating the capacity of either host or lymphoma cells to signal through the IFNγ receptor (IFNγR), we investigated whether the therapeutic effect conferred by vaccine-induced IFNγ is a result of immune cell activation, lymphoma IFNγ sensitivity or a combination of both. We demonstrated that antitumour immunity elicited by vaccination requires IFNγ signalling within host cells but not tumour cells. IFNγR-deficient mice failed to mount an effective antitumour immune response following vaccination despite elevated IFNγ levels. With successive exposure to vaccination, lymphomas acquired an increasingly therapy-resistant phenotype and displayed a reduction in major histocompatibility complex I and CD1d surface expression, which is independent of tumour intrinsic IFNγ signalling. Our results suggest that immunotherapy-induced IFNγ production mainly exerts its therapeutic effect via signalling through host cells, rather than directly to tumour cells in B-NHL. This signifies that intact IFNγ signalling within patients' immune compartment rather than tumour cell sensitivity to IFNγ is more critical for successful treatment. Finally, tumour IFNγ signalling alone does not drive acquired tumour resistance to vaccination, implying that additional immunoediting pathways are responsible for tumour immune escape.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Rory
authors.initials: R
authors.lastname: Rearden
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Amelia
authors.initials: A
authors.lastname: Sah
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Brianna
authors.initials: B
authors.lastname: Doff
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: Sara J
authors.initials: SJ
authors.lastname: McKee
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
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology; D002462:Cell Membrane / Q000378:metabolism; D060467:Disease Resistance / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007109:Immunity; D007371:Interferon-gamma / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000628:therapy*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012008:Recurrence; D015398:Signal Transduction; D013997:Time Factors; D014611:Vaccination
chemical_list: D055610:Antigens, CD1d; D051940:B7-2 Antigen; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma