title: Mycobacteria activate γδ T-cell anti-tumour responses via cytokines from type 1 myeloid dendritic cells: a mechanism of action for cancer immunotherapy.
abstract: Attenuated and heat-killed mycobacteria display demonstrable activity against cancer in the clinic; however, the induced immune response is poorly characterised and potential biomarkers of response ill-defined. We investigated whether three mycobacterial preparations currently used in the clinic (BCG and heat-killed Mycobacterium vaccae and Mycobacterium obuense) can stimulate anti-tumour effector responses in human γδ T-cells. γδ T-cell responses were characterised by measuring cytokine production, expression of granzyme B and cytotoxicity against tumour target cells. Results show that γδ T-cells are activated by these mycobacterial preparations, as indicated by upregulation of activation marker expression and proliferation. Activated γδ T-cells display enhanced effector responses, as shown by upregulated granzyme B expression, production of the T(H)1 cytokines IFN-γ and TNF-α, and enhanced degranulation in response to susceptible and zoledronic acid-treated resistant tumour cells. Moreover, γδ T-cell activation is induced by IL-12, IL-1β and TNF-α from circulating type 1 myeloid dendritic cells (DCs), but not from type 2 myeloid DCs or plasmacytoid DCs. Taken together, we show that BCG, M. vaccae and M. obuense induce γδ T-cell anti-tumour effector responses indirectly via a specific subset of circulating DCs and suggest a mechanism for the potential immunotherapeutic effects of BCG, M. vaccae and M. obuense in cancer.
authors: Department of Clinical Sciences, St. George's University of London, Cranmer Terrace, Tooting Broadway, London, SW17 0RE, UK. dfowler@sgul.ac.uk
authors: Daniel W
authors: DW
authors: Fowler
authors: John
authors: J
authors: Copier
authors: Natalie
authors: N
authors: Wilson
authors: Angus G
authors: AG
authors: Dalgleish
authors: Mark D
authors: MD
authors: Bodman-Smith
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D001500:BCG Vaccine / Q000627:therapeutic use*; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000187:drug effects; D009161:Mycobacterium / Q000276:immunology*; D022423:Myeloid Cells / Q000473:pathology; D009369:Neoplasms / Q000628:therapy*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000382:microbiology*; D014613:Vaccines, Attenuated / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; D001500:BCG Vaccine; D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014613:Vaccines, Attenuated