Optimizing NK Cell-Based Immunotherapy in Myeloid Leukemia: Abrogating an Immunosuppressive Microenvironment.

Natasha Mupeta Kaweme,Fuling Zhou

doi:10.3389/fimmu.2021.683381

Abstract

Natural killer (NK) cells are prominent cytotoxic and cytokine-producing components of the innate immune system representing crucial effector cells in cancer immunotherapy. Presently, various NK cell-based immunotherapies have contributed to the substantial improvement in the reconstitution of NK cells against advanced-staged and high-risk AML. Various NK cell sources, including haploidentical NK cells, adaptive NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, chimeric antigen receptor NK cells, cytokine-induced memory-like NK cells, and NK cell lines have been identified. Devising innovative approaches to improve the generation of therapeutic NK cells from the aforementioned sources is likely to enhance NK cell expansion and activation, stimulate ex vivo and in vivo persistence of NK cells and improve conventional treatment response of myeloid leukemia. The tumor-promoting properties of the tumor microenvironment and downmodulation of NK cellular metabolic activity in solid tumors and hematological malignancies constitute a significant impediment in enhancing the anti-tumor effects of NK cells. In this review, we discuss the current NK cell sources, highlight ongoing interventions in enhancing NK cell function, and outline novel strategies to circumvent immunosuppressive factors in the tumor microenvironment to improve the efficacy of NK cell-based immunotherapy and expand their future success in treating myeloid leukemia.

Highlights

Acute myeloid leukemia (AML) is an aggressive malignant disease of high heterogeneity that remains a deterring challenge to clinicians due to shortened remission duration and high relapse rates associated with the disease
Romee et al demonstrated that the long-lasting increase in functional capacity afforded by memory-like Natural killer (NK) cell differentiation, combined with improved AML recognition, enhanced in vivo expansion and antileukemia responses [27]
NK cells have emerged as contributors to the effect of cytotoxic T lymphocyte-associated protein 4 (CTLA4), LAG3, and PD-1 in cancer patients, suggesting that immune checkpoint receptors regulate NK cell activity under pathological conditions [226]

Summary

Introduction

Acute myeloid leukemia (AML) is an aggressive malignant disease of high heterogeneity that remains a deterring challenge to clinicians due to shortened remission duration and high relapse rates associated with the disease. Expression of high levels of inhibitory molecules, including PD-L1 or PD-L2, on tumor cells, immunosuppressive cells, antigen-presenting cells, and stromal cells in the TME prevent NK cell activation by binding with their respective inhibitory receptors on NK cells, resulting in NK cell exhaustion and dysfunction [119, 120]. TME, tumor microenvironment; NK, natural killer; AML, acute myeloid leukemia; TGF-b, transforming growth factor-b; GLUTS, glucose transporters; A2aR, A2a adenosine receptor; VEGF, vascular endothelial growth factor; IDO, indoleamine 2,3-dioxygenase; NO, nitric oxide; PGE2, prostaglandin E2; IFNg, interferon-g ; IFNa, interferon-a; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIF-a, hypoxia-inducible factor-a; ADCC, antibody-dependent cellular cytotoxicity; mAbs, monoclonal antibodies.

Results

Conclusion