title: Regulation of CD80/B7-1 and CD86/B7-2 molecule expression in human primary acute myeloid leukemia and their role in allogenic immune recognition.
abstract: Clinical data and animal models afford evidence for anti-leukemia immunity in humans, but the interactions critical for blast cell recognition are unresolved. Expression of B7 molecules by antigen-presenting cells (APC) provides co-stimulatory signals to T lymphocytes via CD28 and CTLA-4 which prevent the induction of alloantigen-specific tolerance. Conversely, expression of CD40 ligand by stimulated T cells activates APC via CD40. In human hematological B cell malignancies (follicular lymphoma and chronic lymphocytic leukemia), the defect in alloantigen presentation of tumoral cells can be repaired by up-regulation of B7 and other co-stimulatory molecules via CD40. We studied the role of B7 molecules in alloimmune recognition and the various ways to improve the antitumoral response on peripheral blood leukemic cells from 20 patients with a diagnosis of primary acute myeloid leukemia (AML). We focused on myelo/monocytic M4/M5 French-American-British classification subtypes which are considered as the neoplastic counterpart of normal monocytes, a prototypic APC. In one-way mixed lymphocyte reaction of CD4+ T cells against leukemic cells, differences in B7-1, B7-2 or CD40 expression by AML cells did not induce specific cytokine secretion; interleukin (IL)-2 and interferon (IFN)-gamma were detected but not IL-4, corresponding to a Th1 pattern. Blockade experiments showed that proliferation and IFN-gamma secretion only partially depended on B7 molecules, which in contrast had a pivotal role in IL-2 synthesis. In contrast with murine models which suggest a pivotal role for CD80/B7-1 in the immune response against AML, our data support a greater role for CD86/B7-2, in line with the baseline expression of CD86/B7-2 and lack of CD80/B7-1 on most M4/M5 AML cells. AML cell stimulation via CD40: (1) significantly improved IL-2 secretion but not proliferation of responding T lymphocytes, (2) increased CD54/ICAM-1 expression in three quarters of cases, (3) failed in most cases to induce CD40-specific CD80/B7-1 up-regulation, and (4) had a weak effect on CD86/B7-2 expression. These data contrast with the very efficient up-regulation of both B7 co-stimulatory molecule expression and tumoral cell alloimmune recognition following CD40 stimulation in B cell malignancy models. The role of the defective B7 molecule up-regulation by the CD40 pathway in inefficient tumor immunogenicity of primary AML cells has to be further investigated, in particular using transfection experiments of CD80/B7-1-deficient AML cell lines. From our in vitro data we conclude that B7 molecules play an important role in the alloimmune surveillance of AML as suggested by the high B7 molecule dependency of IL-2 secretion. Nonetheless, the contribution of B7 molecules to alloimmune T cell proliferation against primary AML cells in human and the way to improve it--regulation via CD40 in particular--differ from B cell malignancies and murine models, suggesting the requirement for specific strategies in the development of antitumor immunity.
authors.affiliation: Unité d'Immunologie des Tumeurs, Université de la Méditerranée, Institut Paoli-Calmettes, Marseille, France.
authors.forename: R T
authors.initials: RT
authors.lastname: Costello
authors.forename: F
authors.initials: F
authors.lastname: Mallet
authors.forename: D
authors.initials: D
authors.lastname: Sainty
authors.forename: D
authors.initials: D
authors.lastname: Maraninchi
authors.forename: J A
authors.initials: JA
authors.lastname: Gastaut
authors.forename: D
authors.initials: D
authors.lastname: Olive
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007948:Leukemia, Monocytic, Acute / Q000235:genetics* / Q000378:metabolism; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics* / Q000378:metabolism; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D009000:Monocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D008222:Lymphokines; D008562:Membrane Glycoproteins; D018799:Intercellular Adhesion Molecule-1