New Weapons for Natural Killer Cell Arsenal Against Hematological Malignancies
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cells Review Checkpoint Inhibitors and Engineered Cells: New Weapons for Natural Killer Cell Arsenal Against Hematological Malignancies Massimo Giuliani 1,* and Alessandro Poggi 2 1 Department of Oncology, Luxembourg Institute of Health, Luxembourg City L-1526, Luxembourg 2 Molecular Oncology and Angiogenesis Unit, IRCCS AOU San Martino IST, 16132 Genoa, Italy; [email protected] * Correspondence: [email protected] Received: 1 June 2020; Accepted: 25 June 2020; Published: 29 June 2020 Abstract: Natural killer (NK) cells represent one of the first lines of defense against malignant cells. NK cell activation and recognition are regulated by a balance between activating and inhibitory receptors, whose specific ligands can be upregulated on tumor cells surface and tumor microenvironment (TME). Hematological malignancies set up an extensive network of suppressive factors with the purpose to induce NK cell dysfunction and impaired immune-surveillance ability. Over the years, several strategies have been developed to enhance NK cells-mediated anti-tumor killing, while other approaches have arisen to restore the NK cell recognition impaired by tumor cells and other cellular components of the TME. In this review, we summarize and discuss the strategies applied in hematological malignancies to block the immune check-points and trigger NK cells anti-tumor effects through engineered chimeric antigen receptors. Keywords: NK cells; hematological malignancies; check-point inhibitors; CAR NK cells; antibodies; immunotherapy 1. Tumor-Mediated NK Cell Exhaustion in Hematological Malignancies NK cells represent one of the first lines of defense against malignant cells. Their immune- surveillance ability is mediated by the expression of activating receptors such as the natural killer group (NKG)2D, DNAX accessory molecule (DNAM)-1, and the natural cytotoxic receptors (NCRs) such as natural killer protein (NKp)30, NKp44, and NKp46 [1–5]. NK cell recognition is also dependent by an array of inhibitory receptors, such as killer inhibitory receptors (KIRs) and NKG2A molecule [6]. Once the target is acquired in the viewfinder, NK cells secrete cytotoxic granules (as granzymes and perforin) and cytokines (as tumor necrosis factor (TNF)-α and interferon (IFN)-γ), which lead to the killing of the target. Several molecular mechanisms have been developed in hematological malignancies to allow tumor cells to elude and escape from NK cell-mediated recognition. Some of these mechanisms are represented by the inhibition of tumor antigen presentation, expression of immune checkpoint ligands as programmed death ligand-1 (PD-L1), secretion of suppressive factors like interleukin (IL)-10, soluble human leukocyte antigen (HLA)-G, transforming growth factor (TGF)-β, indoleamine 2,3-dioxygenase (IDO), recruitment and polarization of immunosuppressive cells as macrophages, regulatory T cells (Tregs), myeloid derived suppressor cells (MDSC), and mesenchymal stromal cells (MSC). Altogether these cells, with the tumor cells themselves, are present inthe tumor microenvironment (TME) [7–11] (Figure1). Another major molecular mechanism used by tumor cells to impair NK cell recognition and activation is based on the expression of inhibitory (as major histocompatibility complex (MHC) class Cells 2020, 9, 1578; doi:10.3390/cells9071578 www.mdpi.com/journal/cells Cells 2020, 9, 1578 2 of 31 I molecules)Cells 2020, 9, x and the release in a soluble form of ligands (such as MHC class I polypeptide–related2 of 29 sequence (MIC) A/B and UL16 binding protein (ULBP1-6) for NK cell-activating receptors [12,13]. The(such TME as isMHC insomuch class I polypept efficientide–related that NK cells sequence isolated (MIC) from A/B patients and UL16 with binding hematological protein (ULBP1-6) malignancies displayfor NK multiple cell-activatin abnormalities.g receptors In [12,1 particular,3]. The TME NK cells is insomuch isolated fromefficient chronic that NK myeloid cells leukemiaisolated from (CML), patients with hematological malignancies display multiple abnormalities. In particular, NK cells acute lymphocytic leukemia (ALL), myelodysplastic syndromes (MDS), and chronic lymphocytic isolated from chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), myelodysplastic leukemia (CLL) patients suffer a decreased cell number, activating receptors expression, and cytokines syndromes (MDS), and chronic lymphocytic leukemia (CLL) patients suffer a decreased cell number, secretion [14–19]. Similar tumor-mediated impairment of NK cell functions has been also described in activating receptors expression, and cytokines secretion [14–19]. Similar tumor-mediated impairment acute myeloid leukemia (AML) and multiple myeloma (MM) patients [15–17,20–24]. This is associated of NK cell functions has been also described in acute myeloid leukemia (AML) and multiple myeloma with(MM) an patients impaired [15–1 polarization7,20–24]. This of cytolytic is associated granules with toward an impaired the immunological polarization of synapse cytolytic against granules tumor cellstoward [16, 23the,25 immunological,26] and increased synapse expression against of tumor inhibitory cells [16,23,25,26] receptors like and NKG2A, increased programmed expression deathof receptorinhibitory (PD)-1 receptors and KIRs like NKG2A, [27–30]. programmed Interestingly, death it has receptor been shown (PD)-1 in an CLLd KIRs patients [27–30]. that Interestingly, NK cells losing NKp30 on their surface acquire the inhibitory receptor T-cell immunoglobulin and mucin domain (TIM)-3, which was correlated with poor prognostic factors [31]. FigureFigure 1. 1.Strategies Strategies usedused byby the tumor microenvironment(TME) microenvironment (TME) to toimpair impair natural natural killer killer (NK) (NK) cell cell immuno-surveillanceimmuno-surveillance in hematological hematological malignancies. malignancies. (a) (Tumora) Tumor cells cells secrete secrete several several chemokines chemokines as asCXCL12 CXCL12 to torecruit recruit suppressive suppressive cells cellssuch as such myeloid as myeloid derived derivedsuppressors suppressors cells (MDSCs) cells and (MDSCs) tumor– and tumor–associatedassociated macrophages macrophages (TAMs). (TAMs). These cells These inhibit cells NK inhibit cell functions NK cell functionsby secreting by soluble secreting factors soluble factorssuch as such interleukin as interleukin (IL)-10, (IL)-10,transforming transforming growth factor growth (TGF)- factorβ, (TGF)-reactiveβ ,oxygen reactive species oxygen (ROS), species (ROS),arginine arginine and nitric and nitricoxide oxidesynthase synthase (NOS), (NOS), or through or through the expression the expression of inhibitory of inhibitory receptors receptors as asprogrammed programmed death-ligand death-ligand (PD-L)1 (PD-L)1 or orrelease release of ofligan ligandsds for forNK NK activating activating receptors. receptors. In addition, In addition, MDSCs and TAMs can recruit other suppressive cells like regulatory T cells (Tregs), which indirectly MDSCs and TAMs can recruit other suppressive cells like regulatory T cells (Tregs), which indirectly contribute to induce an exhausted and dysfunctional profile in NK cells. (b) Tumor cells secrete contribute to induce an exhausted and dysfunctional profile in NK cells. (b) Tumor cells secrete immunosuppressive molecules whose impair NK cell proliferation, activation and cytotoxicity, such immunosuppressive molecules whose impair NK cell proliferation, activation and cytotoxicity, such as as TGF-β, prostaglandin (PG)E-2, indoleamine 2,3-dioxygenase (IDO) and soluble human leukocyte TGF-β, prostaglandin (PG)E-2, indoleamine 2,3-dioxygenase (IDO) and soluble human leukocyte antigen (HLA)-G. A mechanism used by hematological malignancies to avoid NK cell-mediated antigen (HLA)-G. A mechanism used by hematological malignancies to avoid NK cell-mediated recognition is the expression of inhibitory receptors as PD-L1 Also, tumor cells can secrete natural recognition is the expression of inhibitory receptors as PD-L1 Also, tumor cells can secrete natural killer killer group (NKG)2DLs, which impair the interaction between tumor and NK cells affecting the group (NKG)2DLs, which impair the interaction between tumor and NK cells affecting the positive positive signal induced by NKG2D. (c) Mesenchymal stromal cells (MSC) decrease granule c signalexocytosis, induced cytokines by NKG2D. secretion ( ) Mesenchymal and cytotoxicity stromal of NK cells cells (MSC) through decrease the secretion granule of exocytosis,soluble factors cytokines as β secretionPGE-2, TGF- and β cytotoxicity and soluble of HLA-G NK cells and through through thethe secretionexpression of of soluble PD-L1 and factors HLA-G. as PGE-2, TGF- and soluble HLA-G and through the expression of PD-L1 and HLA-G. 2. Current Advanced Therapy in Hematological Malignancies Cells 2020, 9, 1578 3 of 31 2. Current Advanced Therapy in Hematological Malignancies Cells 2020, 9, x 3 of 29 Once effectors cells infiltrate the tumor site, they have to fight both tumor cells and the other componentsOnce effectors of the TME. cells Toinfiltrate that end, the thetumor purpose site, they of recent have to therapeutic fight both strategies tumor cells is and to improve the other NK cellcomponents survival, proliferation, of the TME. To activation, that end, andthe purpose cytotoxic offunctions recent therapeutic in a hostile strategies and immune-suppressive is to improve NK environment.cell survival, Over proliferation, the years, activation, several approaches