NK Cell Recognition of Leukemia Blasts and IL-2 Therapy

描述(申请人提供)：大约20-25%的急性髓系白血病(AML)患者在强化化疗后治愈。白介素2用于AML缓解期患者，已被研究为一种潜在的减少复发和改善预后的手段。IL-2在体内扩增并激活自然杀伤(NK)细胞，自然杀伤(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方面的重要性的了解表明，并不是所有的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裂解是由激活和抑制表面受体的平衡调节的，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细胞激活的NKG2D受体的配体。此外，AML对这些配体的表达是异质性的，这与疾病的分子异质性是一致的。我们推测，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对自体NK细胞溶解敏感，而具有这种白血病母细胞的患者最有可能从IL-2治疗中受益。为了验证这一假说，我们建议对参加癌症研究的AML患者和进行IL-2免疫治疗的B组白血病患者的样本进行相关研究，探讨白血病细胞上已知重要的NK细胞激活和抑制配体的表达、AML细胞对自体IL-2扩增的NK细胞的体外易感性与临床结果的关系。具体地说，我们的目标是1)将体内扩增的NK细胞对治疗前AML细胞的体外裂解与IL-2治疗后的无复发生存(RFS)相关联，2)将AML原始细胞上抑制性(MHC I类)和激活配体的表达与RFS相关联，以及3)比较初诊和复发的白血病原始细胞对NK细胞裂解的易感性。我们的研究结果可能提供一种方法来确定哪些AML患者对IL-2治疗敏感，因此，最终可能有助于更好地选择基于NK细胞的治疗患者。

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.