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。白血病缓解期患者使用白细胞介素(IL)-2作为潜在减少复发和改善预后的手段已被研究。IL-2在体内扩张并激活自然杀伤（NK）细胞，NK细胞不需要识别白血病特异性抗原就能杀死白血病细胞。然而，最近对NK细胞受体（NKR）在识别和裂解靶细胞中的重要性的了解表明，并非所有患者都可能从这种免疫治疗策略中受益。NK细胞对白血病细胞的识别和溶解是通过激活和抑制表面受体的平衡来调节的，这些受体与靶细胞上特定的MHC I类和I类配体相互作用。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NKG2D受体的配体。此外，AML中这些配体的表达是异质的，与疾病的分子异质性保持一致。我们假设只有表达高水平激活配体和/或低水平抑制配体的白血病细胞才容易受到自体NK细胞溶解的影响，并且具有这种白血病母细胞的患者最有可能从IL-2治疗中获益。为了验证这一假设，我们建议对参与IL-2免疫治疗的癌症和白血病B组研究的AML患者样本进行相关研究，研究已知重要NK细胞激活和抑制配体在白血病母细胞上的表达、AML细胞对自体IL-2扩增NK细胞的体外敏感性以及临床结果之间的关系。具体来说，我们的目标是1)将IL-2治疗前AML母细胞体外裂解与IL-2治疗后无复发生存（RFS）联系起来，2)将AML母细胞上抑制性（MHC类I）和激活性配体的表达与RFS联系起来，3)比较诊断和复发时获得的白血病母细胞对NK细胞裂解的敏感性。我们的研究结果可能提供一种方法来确定哪些AML病例对IL-2治疗敏感，因此，最终可能有助于更好地选择基于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.