REGULATION OF CD80 B7-1 AND CD86/B7-2 MOLECULE EXPRESSION IN HUMAN PRIMARY ACUTE MYELOID-LEUKEMIA AND THEIR ROLE IN ALLOGENIC IMMUNE RECOGNITION/

Clinical data and animal models afford evidence for anti-leukemia immu nity in humans, but the interactions critical for blast cell recogniti on are unresolved. Expression of B7 molecules by antigen-presenting ce lls (APC) provides co-stimulatory signals to T lymphocytes via CD28 an d CTLA-4 which prevent the induction of alloantigen-specific tolerance , Conversely, expression of CD40 ligand by stimulated T cells activate s 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 t he antitumoral response on peripheral blood leukemic cells from 20 pat ients with a diagnosis of primary acute myeloid leukemia (AML). We foc used on myelo/monocytic M4/M5 French-American-British classification s ubtypes which are considered as the neoplastic counterpart of normal m onocytes, a prototypic APC. In one-way mixed lymphocyte reaction of CD 4(+) T cells against leukemic cells, differences in B7-1, B7-2 or CD40 expression by AML cells did not induce specific cytokine secretion; i nterleukin (IL)-2 and interferon (IFN)-gamma were detected but not IL- 4, corresponding to a Th1 pattern. Blockade experiments showed that pr oliferation and IFN-gamma secretion only partially depended on B7 mole cules, which in contrast had a pivotal role in IL-2 synthesis. In cont rast 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 C D86/B7-2, in line with the baseline expression of CD86/B7-2 and lack o f CD80/B7-1 on most M4/M5 AML cells. AML cell stimulation via CD40: (1 ) significantly improved IL-2 secretion but not proliferation of respo nding T lymphocytes, (2) increased CD54/ICAM-1 expression in three qua rters 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 recogni tion following CD40 stimulation in B cell malignancy models. The role of the defective B7 molecule up-regulation by the CD40 pathway in inef ficient tumor immunogenicity of primary AML cells has to be further in vestigated, in particular using transfection experiments of CD80/B7-1- deficient AML cell lines. From our in vitro data we conclude that B7 m olecules play an important role in the alloimmune surveillance of AML as suggested by the high B7 molecule dependency of IL-2 secretion. Non etheless, the contribution of B7 molecules to alloimmune T cell prolif eration against primary AML cells in human and the way to improve it - regulation via CD40 in particular - differ from B cell malignancies a nd murine models, suggesting the requirement for specific strategies i n the development of antitumor immunity.