NK Cell Recognition of Leukemia Blasts and IL-2 Therapy

描述（由申请人提供）：大约20-25%的急性髓性白血病（AML）患者在强化化疗后治愈。白细胞介素（IL）-2，给予缓解期AML患者，已被研究作为一种手段，可能减少复发和改善结果。IL-2在体内扩增并激活自然杀伤（NK）细胞，这种细胞不需要识别白血病特异性抗原即可杀死白血病细胞。然而，最近对NK细胞受体（NKR）识别和裂解靶细胞的重要性的认识表明，并非所有患者都可能从这种免疫治疗策略中获益。NK细胞对白血病细胞的识别和裂解受活化和抑制性表面受体的平衡调节，所述活化和抑制性表面受体与靶细胞上的特异性MHC I类和I类样配体相互作用。我们的初步数据确实表明，原代AML细胞，而不仅仅是细胞系，表达NK细胞活化NKG 2D受体的配体。此外，AML中这些配体表达是异质的，与疾病的分子异质性一致。我们假设只有表达高水平活化配体和/或低水平抑制配体的白血病细胞对自体NK细胞溶解敏感，并且具有这种白血病原始细胞的患者最有可能从IL-2治疗中获益。为了研究这一假设，我们建议对从参加IL-2免疫治疗的癌症和白血病B组研究的AML患者中获得的样本进行相关研究，研究白血病原始细胞上已知的重要NK细胞活化和抑制配体的表达、AML细胞对自体IL-2扩增的NK细胞的体外敏感性和临床结果之间的关系。具体而言，我们的目标是1）将IL-2体内扩增的NK细胞对治疗前AML原始细胞的体外裂解与IL-2治疗后的无复发生存期（RFS）相关联，2）将AML原始细胞上抑制性（MHC I类）和活化配体的表达与RFS相关联，以及3）比较诊断时和复发时获得的白血病原始细胞对NK细胞裂解的敏感性。我们的研究结果可能提供一种方法，以确定哪些AML病例子集对IL-2治疗敏感，因此，最终可能有助于更好地选择患者进行基于NK细胞的治疗。

DESCRIPTION (provided by applicant): Approximately 20-25% of patients with acute myeloid leukemia (AML) are cured following intensive chemotherapy. Interleukin (IL)-2, administered to AML patients in remission, has been investigated as a means of potentially reducing relapse and improving outcome. IL-2 in vivo expands and activates natural killer (NK) cells, which do not require the recognition of leukemia-specific antigens for killing of leukemic cells. Recent understanding of the importance of NK cell receptors (NKR) for the recognition and lysis of target cells, however, suggests that not all patients are likely to benefit from this immunotherapy strategy. Recognition and lysis of leukemic cells by NK cells is regulated by a balance of activating and inhibitory surface receptors that interact with specific MHC class I and class I-like ligands on target cells. Our preliminary data indeed suggests that primary AML cells, and not only cell lines, express ligands to the activating NKG2D receptor of NK cells. Furthermore, that expression of these ligands by AML is heterogeneous, in keeping with the molecular heterogeneity of the disease. We hypothesize that only leukemic cells that express high levels of activating ligands and/or low levels of inhibitory ligands are susceptible to autologous NK cell lysis, and that patients with such leukemic blasts are those most likely to benefit from IL-2 therapy. To investigate this hypothesis, we propose to perform correlative studies on samples procured from AML patients enrolled on Cancer and Leukemia Group B studies of IL-2 immunotherapy, investigating the relationship between the expression of known important NK cell activating and inhibitory ligands on leukemic blasts, in vitro susceptibility of AML cells to autologous IL-2 expanded NK cells, and clinical outcome. Specifically, we aim to 1) Correlate the in vitro lysis of pre-treatment AML blasts by IL-2 in vivo expanded NK cells with relapse-free survival (RFS) following IL-2 therapy, 2) Correlate the expression of inhibitory (MHC class I) and activating ligands on AML blasts with RFS, and 3) Compare the susceptibility to NK cell lysis of leukemic blasts obtained at diagnosis and at relapse. The results of our studies may provide a means of identifying which subset of AML cases are susceptible to IL-2 therapy, and therefore, may ultimately assist in the better selection of patients for NK cell-based therapies.