Natural killer cell cytotoxicity is a predictor of outcome for patients with high risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia treated with azacytidine

Tsirogianni, Maria; Grigoriou, Eirini; Kapsimalli, Violetta; Dagla, Kleopatra; Stamouli, Maria; Gkirkas, Konstantinos; Konsta, E.; Karagiannidou, Angeliki; Gkodopoulos, Konstantinos; Stavroulaki, Georgia; Pappa, Vassiliki; Angelopoulou, Maria K.; Lowdell, Mark W.; Tsirigotis, Panagiotis

doi:10.1080/10428194.2019.1581935

Cited by 13 publications

(8 citation statements)

References 20 publications

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“…In a follow-up study, the investigators identified that the efficacy against AML was linked to a dimorphism in HLA-B at amino acid −21 that has an impact on NK cell education (92), again supporting a critical role for NK cells in this disease. In a separate study, the outcome following treatment of AML and high-risk MDS with the hypomethylating agent Azacytidine could be predicted by NK cell function after three to six cycles (93). Taken together, NK cell function is often suppressed upon diagnosis and at disease progression of myeloid malignancies, but restored in remission.…”

Section: Nk Cell Function and Maturation In Patients With Myeloid Malmentioning

confidence: 99%

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

2019

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Natural killer (NK) cells are large granular lymphocytes involved in our defense against certain virus-infected and malignant cells. In contrast to T cells, NK cells elicit rapid anti-tumor responses based on signals from activating and inhibitory cell surface receptors. They also lyse target cells via antibody-dependent cellular cytotoxicity, a critical mode of action of several therapeutic antibodies used to treat cancer. A body of evidence shows that NK cells can exhibit potent anti-tumor activity against chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS). However, disease-associated mechanisms often restrain the proper functions of endogenous NK cells, leading to inadequate tumor control and risk for disease progression. Although allogeneic NK cells can prevent leukemia relapse in certain settings of stem cell transplantation, not all patients are eligible for this type of therapy. Moreover, remissions induced by adoptively infused NK cells are only transient and require subsequent therapy to maintain durable responses. Hence, new strategies are needed to trigger full and durable anti-leukemia responses by NK cells in patients with myeloid malignancies. To achieve this, we need to better understand the interplay between the malignant cells, their microenvironment, and the NK cells. This review focuses on mechanisms that are involved in suppressing NK cells in patients with myeloid leukemia and MDS, and means to restore their full anti-tumor potential. It also discusses novel molecular targets and approaches, such as bi- and tri-specific antibodies and immune checkpoint inhibitors, to redirect and/or unleash the NK cells against the leukemic cells.

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Section: Nk Cell Function and Maturation In Patients With Myeloid Malmentioning

confidence: 99%

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

2019

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“…In contrast, an impaired NK cell-mediated cytotoxicity and/or abnormal expression of surface receptors has been observed in patients suffering from leukemia [14][15][16]. Notwithstanding, the studies have been conducted mostly in patients with chronic or myeloid leukemias [17][18][19]. A previous study has reported that peripheral blood NK cells from B-ALL patients have a compromised cytotoxicity towards K562 and autologous blasts.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of NK cells in Mexican pediatric patients with acute lymphoblastic leukemia: Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

et al. 2020

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“…In a flow cytometry-based analysis of 130 AML samples, increased frequency of NK cells (>5%) was found to be an independent predictor of improved overall and disease-free survival in response to standard of care treatment ( 69 ). Additionally, degree of NK cytotoxicity was a predictor of overall survival in response to the hypomethylating agent azacytidine ( 70 ). Together, these findings have led to the hypothesis that NK activity as opposed to direct effects of chemotherapy were responsible for durable remissions in AML patients, or that certain standard-of-care treatments work in part by potentiating anti-leukemic NK responses.…”

Section: Nk Cells In Amlmentioning

confidence: 99%

Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML

Kent,

Crump,

Davila

2023

Front. Immunol.

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Acute myeloid leukemia (AML) remains an elusive disease to treat, let alone cure, even after highly intensive therapies such as stem cell transplants. Adoptive cell therapeutic strategies based on conventional alpha beta (αβ)T cells are an active area of research in myeloid neoplasms given their remarkable success in other hematologic malignancies, particularly B-cell-derived acute lymphoid leukemia, myeloma, and lymphomas. Several limitations have hindered clinical application of adoptive cell therapies in AML including lack of leukemia-specific antigens, on-target-off-leukemic toxicity, immunosuppressive microenvironments, and leukemic stem cell populations elusive to immune recognition and destruction. While there are promising T cell-based therapies including chimeric antigen receptor (CAR)-T designs under development, other cytotoxic lymphocyte cell subsets have unique phenotypes and capabilities that might be of additional benefit in AML treatment. Of particular interest are the natural killer (NK) and unconventional T cells known as invariant natural killer T (iNKT) and gamma delta (γδ) T cells. NK, iNKT, and γδT cells exhibit intrinsic anti-malignant properties, potential for alloreactivity, and human leukocyte-antigen (HLA)-independent function. Here we review the biology of each of these unconventional cytotoxic lymphocyte cell types and compare and contrast their strengths and limitations as the basis for adoptive cell therapies for AML.

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Natural killer cell cytotoxicity is a predictor of outcome for patients with high risk myelodysplastic syndrome and oligoblastic acute myeloid leukemia treated with azacytidine

Cited by 13 publications

References 20 publications

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

Natural Killer Cells in Myeloid Malignancies: Immune Surveillance, NK Cell Dysfunction, and Pharmacological Opportunities to Bolster the Endogenous NK Cells

Functional characterization of NK cells in Mexican pediatric patients with acute lymphoblastic leukemia: Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML

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