title: Human CD80/IL2 lentivirus transduced acute myeloid leukaemia cells enhance cytolytic activity in vitro in spite of an increase in regulatory CD4+ T cells in a subset of cultures.
abstract: Immunotherapeutic strategies are increasingly being explored as a method of enhancing anti-tumour immune responses in patients with acute myeloid leukaemia (AML). Regulatory CD4(+) T cells (Tregs) suppress effector T and natural killer (NK) cells and therefore pose a potential challenge to the efficacy of immunotherapy. AML cells transduced with a lentivirus expressing CD80 (B7.1) and IL2 (LV-CD80/IL2) are capable of stimulating T and NK cell cytotoxicity in vitro. This study examines the effect of CD80/IL2 modified AML cells on Treg number and function. We report a significant increase in the number of CD8(+) T cells (P = 0.046) CD3(-)CD56(+) NK cells (P = 0.028) and CD3(+)CD4(+)CD25(high)Foxp3(+) Tregs (P = 0.043) following stimulation for 7 days with allogeneic LV-CD80/IL2 AMLs. In contrast, autologous LV-CD80/IL2 AML cell cultures provide a weaker stimulation with a lower number of CD8(+) T cells (P = 0.011) and no change in NK cell or Treg numbers. However, an increase in cytotoxic CD8(+) T cells and NK cells are detected following both allogeneic and autologous LV-CD80/IL2 stimulation as demonstrated by an increase in IFN-gamma and CD107a expression. Despite the presence of increased numbers of Tregs with suppressive activity in a subset of cultures, increased lysis of unmodified AMLs was still achieved following allogeneic (day 0, 2.2%; day 7, 20.4%) and more importantly, autologous LV-CD80/IL2 culture in which AML patients had recently received intensive chemotherapy (day 0, 0%; day 7, 16%). Vaccination with LV-CD80/IL2 therefore provides a potential strategy to enhance anti-leukaemia immune responses without a concomitant stimulation of Treg-mediated inhibition of cytotoxic immunological responses.
authors.affiliation: Department of Haematological Medicine, King's College London, Rayne Institute, 123 Coldharbour Lane, London, SE5 9NU, UK. wendy.2.ingram@kcl.ac.uk
authors.forename: Wendy
authors.initials: W
authors.lastname: Ingram
authors.forename: Shahram
authors.initials: S
authors.lastname: Kordasti
authors.forename: Lucas
authors.initials: L
authors.lastname: Chan
authors.forename: Linda D
authors.initials: LD
authors.lastname: Barber
authors.forename: Gee J
authors.initials: GJ
authors.lastname: Tye
authors.forename: Nicola
authors.initials: N
authors.lastname: Hardwick
authors.forename: Ghulam J
authors.initials: GJ
authors.lastname: Mufti
authors.forename: Farzin
authors.initials: F
authors.lastname: Farzaneh
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000276:immunology; D016086:Lentivirus / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014161:Transduction, Genetic; D019076:Transgenes / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D007376:Interleukin-2; D007371:Interferon-gamma