Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia

Martner, Anna; Rydström, Anna; Riise, Rebecca; Aurelius, Johan; Anderson, Harald; Brüne, Martin; Foà, Robin; Hellstrand, Kristoffer; Thorén, Fredrik B.

doi:10.1080/2162402x.2015.1041701

Cited by 36 publications

(66 citation statements)

References 48 publications

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“…A phase 3 clinical trial using low-dose interleukin-2 combined with histamine dihydrochloride as maintenance therapy for AML demonstrated improved leukemia-free survival compared with no maintenance, an effect that was associated with peripheral blood NK cell expansion and upregulation of the activating natural cytotoxicity receptors NKp30 and NKp46, suggesting that NK cell activation against AML likely contributed to the observed survival benefit. 34,35 Our results suggest that an alternative approach to prevent AML relapse may be to therapeutically enhance the expression of activating NKRLs on residual AML blasts or to reduce inhibitory NKRL signaling, thereby swaying the balance of NK cell signaling toward a more activating pattern. Rohner and coworkers reported that azacitidine upregulated ULBP1 expression on AML H60 blasts when used in combination with interferon-g, resulting in improved sensitivity to NK-mediated killing via NKG2D signaling.…”

Section: Discussionmentioning

confidence: 92%

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy

Mastaglio¹,

Wong

Perera

et al. 2018

Blood Advances

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Natural killer (NKs) cells provide rapid responses to viral-infected and malignant cells, including acute myeloid leukemia (AML) blasts. The balance among inhibitory and activating signals, delivered by multiple interactions between ligands on target cells and NK receptors, determines the posture of the NK cell response to either one of target cell elimination or tolerance. The aim of this work was to study the influence of the differential expression of activating and inhibitory NK receptor ligands (NKRLs) by leukemic blasts on clinical outcome in newly diagnosed AML patients. Leukemic cells and clinical data from 66 patients undergoing induction chemotherapy were obtained from the Australasian Leukemia Lymphoma Group tissue bank. Expression of 6 activating (MICA, MICAB, CD155, CD112, ULBP1, and ULBP2/5/6) and 3 inhibitory (HLA class I, PD-L1, and PD-L2) NKRLs was analyzed by flow cytometry. AML blasts displayed heterogeneous expression of NKRLs. MICA, CD112, and ULBP1 were most frequently expressed. ULBP1 expression was significantly associated with improved 2-year overall survival (51.4% vs 11.4%), relapse-free survival (42.5% vs 10.0%), and reduced relapse (44.1% vs 78.6%). We calculated a net score of activating minus inhibitory ligands and demonstrated that the expression of an overall activating NK ligand phenotype was associated with superior 2-year overall survival (59.6% vs 24.4%) and reduced relapse (31.5% vs 68.2%). Our study provides clinical evidence for the role of NK cell-mediated immunoediting against AML, mediated by the expression of NKRLs on blasts, and supports investigation into strategies to enhance NK cell function to improve outcomes in patients with AML.

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Section: Discussionmentioning

confidence: 92%

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy

Mastaglio¹,

Wong

Perera

et al. 2018

Blood Advances

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“…Table 1 provides information about the prior induction and consolidation chemotherapy. Further patient characteristics are accounted for in previous publications [17,18,27]. In this single-armed multicenter phase IV study, patients received 10 consecutive 21-d cycles of HDC and low-dose IL-2 for 18 months or until relapse or death using a regime identical to that employed in a previous phase III trial [28].…”

Section: Clinical Trial Patients Study Design and Objectivesmentioning

confidence: 99%

“…The sensitivity of AML cells to the anti-leukemic activity of cytotoxic lymphocytes such as T cells and NK cells [6][7][8][9][10] along with the purported role of these immune effector cells in the surveillance of leukemic cells [11,12] have inspired the development of strategies to boost cellular immunity in the post-consolidation phase for relapse prevention [13][14][15][16]. The NOX2 inhibitor histamine dihydrochloride (HDC) in conjunction with the T and NK cell activating cytokine interleukin-2 (HDC/IL-2) is approved in AML for relapse prevention in Europe, and recent studies imply that aspects of T and NK cell immunity are relevant to the clinical efficiency of this combinatorial immunotherapy [16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Anthracycline-based consolidation may determine outcome of post-consolidation immunotherapy in AML

Aurelius

Möllgård

Kiffin

et al. 2019

Leukemia & Lymphoma

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Consolidation chemotherapy in acute myeloid leukemia (AML) aims at eradicating residual leukemic cells and mostly comprises high-dose cytarabine with or without the addition of anthracyclines, including daunorubicin. Immunogenic cell death (ICD) may contribute to the efficacy of anthracyclines in solid cancer, but the impact of ICD in AML is only partly explored. We assessed aspects of ICD, as reflected by calreticulin expression, in primary human AML blasts and observed induction of surface calreticulin upon exposure to daunorubicin but not to cytarabine. We next assessed immune phenotypes in AML patients in complete remission (CR), following consolidation chemotherapy with or without anthracyclines. These patients subsequently received immunotherapy with histamine dihydrochloride (HDC) and IL-2. Patients who had received anthracyclines for consolidation showed enhanced frequencies of CD8 þ T EM cells in blood along with improved survival. We propose that the choice of consolidation therapy prior to AML immunotherapy may determine clinical outcome. ARTICLE HISTORY

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“…After this work has been submitted, two additional reports from the Hellstrand group independently described an expansion of CD56 bright CD16 neg cells in HDC plus IL-2 treated AML patients [46, 47], but the CD56 bright CD16 low cells were not separately investigated in these studies. Furthermore, somewhat higher intensities of expression of the NCR NKp30 and NKp46 were observed after 3 weeks of treatment and the data supported that a high expression of NKp30 and NKp46 before and during therapy in older patients is a predictor of leukemia-free and overall survival.…”

Section: Discussionmentioning

confidence: 99%

Maintenance therapy with histamine plus IL-2 induces a striking expansion of two CD56bright NK cell subpopulations in patients with acute myeloid leukemia and supports their activation

et al. 2016

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Histamine dihydrochloride (HDC) plus IL-2 has been proposed as a novel maintenance-immunotherapy in acute myeloid leukemia (AML). We analyzed the immunophenotype and function of natural killer (NK) cells in blood of AML patients treated after chemotherapy with HDC plus IL-2. The treatment caused a striking expansion of CD56brightCD16neg and CD56brightCD16low NK cell subpopulations. A reduced NK cell fraction recovered and high proportions of cells expressed the activating receptors NKG2D, NKp30, and NKp46. Concomitantly, KIR-expressing NK cells were reduced and NK cells with inhibitory NKG2A/CD94 receptors increased beyond normal levels. In addition, the immunotherapy-induced NK cells exhibited high capacity to produce IFN-γ and to degranulate. Furthermore, we provide evidence from subsequent in vitro studies that this is caused in part by direct effects of IL-2 on the CD56bright cells. IL-2 specifically induced proliferation of both CD56bright subpopulations, but not of CD56dim cells. It further preserved the expression of activating receptors and the capacity to produce IFN-γ and to degranulate. These data suggest that therapy with HDC plus IL-2 supports the reconstitution of a deficient NK cell fraction through the specific amplification of CD56bright NK cells giving rise to a functional NK cell compartment with high potential to combat leukemic disease.

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Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia

Cited by 36 publications

References 48 publications

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy

Anthracycline-based consolidation may determine outcome of post-consolidation immunotherapy in AML

Maintenance therapy with histamine plus IL-2 induces a striking expansion of two CD56bright NK cell subpopulations in patients with acute myeloid leukemia and supports their activation

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