2516 We have recently reported that STI571 has not only a tumor cell autonomous effect but also acts on host dendritic cells (DC) to promote natural killer (NK) cell activation and NK cell-dependent antitumor effects in mice. Moreover, about 50% of gastrointestinal stromal tumor (GIST) bearing patients undergoing therapy with STI571 acquire NK cell activation correlating with clinical outcome. The study of the Time To Progression (TTP) for 43 patients that benefited from a median follow up of 13.2 months in both cohorts of GIST, those exhibited enhanced NK cell functions (22/43) at 2 months of Gleevec versus those who did not (21/43) revealed that TTP is significantly longer in patients with NK cell activation (Log Rank Test, p=0.03). The potential associated prognostic factors: type of c-kit mutation, extra-gastric primary tumor, haemoglobin level < 7 g/dL, performance status over 2 and pulmonary metastases at entry, were all comparable in these two cohorts. The lack of STI571-mediated NK cell induction found in the other 50% of cases could be assigned to the presence of high numbers of CD4+CD25highregulatory T cells (Treg) in blood at entry, which were shown, by us, to inhibit NK cell effector functions in human ex-vivo and in-vitro. The mean percentages of Treg among CD3+CD4+ T cells in GIST patients displaying NK cell induction were not elevated as compared with normal volunteers (1.1% ± 0.3% vs 1.2% ± 0.4%, respectively, p = 0.5) whereas these yields were increased by three fold in the group of patients with no NK cell induction (3.2% ± 0.8%, p = 0.02). We finally found that the combination of immunopotentiating dosages of cyclophosphamide, aimed at reducing Treg function, with STI571 was synergistic in a mouse (C57BL/6) model of lung melanoma (B16F10 cells) metastases. Altogether, NK cell activation is a novel surrogate marker of efficacy of STI571 which is critical for TTP and could be enhanced by pre-treatment of GIST patients with Treg inhibitors. No significant financial relationships to disclose.