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Human NK cells and NK receptors夽 Francesca Bellora a , Roberta Castriconi a , Alessandra Dondero a , Paolo Carrega b , Alberto Mantovani c , Guido Ferlazzo d , Alessandro Moretta a , Cristina Bottino a,b,∗ a

Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Via L.B. Alberti 2, 16132 Genova, Italy Istituto Giannina Gaslini, L.go G. Gaslini 5, 16147 Genova, Italy Istituto Clinico Humanitas IRCCS and Dipartimento di Biotecnologie e Medicina Traslazionale, Università degli Studi di Milano, Via Manzoni 56, Rozzano, Milano, Italy d Dipartimento di Patologia Umana, Università degli Studi di Messina and A.O.U. Policlinico “G.Martino”, Via Consolare Valeria 1, 98125 Messina, Italy b

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Article history: Received 23 October 2013 Accepted 13 December 2013 Available online xxx Keywords: Human NK cells Receptors Ligands Subsets Migration Anti-tumor activity

a b s t r a c t In early seventies “natural killer (NK) cells”, a third lymphocyte subset was discovered that revealed an unexpected ability to kill syngeneic and allogeneic tumor targets, thus emerging as the most potent non-specific cytotoxic cells in both human and mouse. Decades of research revealed the multifaceted nature of these cells. Now we know that NK cells are highly specific cells able to discriminate between self (which is spared) and non-self (which is attacked). Most of the specific and non HLA-specific surface receptors involved in NK cell recognition and function have been identified and, to date, only few of them still remain orphans. We also know that NK cells contribute to both innate and adaptive immune responses, interact with other immune cell types and release type 1 cytokines and chemokines. Moreover, fundamental data are accumulating on NK cell development and migration under both physiological and pathological conditions. The time is arrived to exploit these cells in the cure of cancer patients. While encouraging results emerged in hematological malignances, the road to treat solid tumors using NK cells is still covered by obstacles that hamper their function and that just begin to be unveiled. © 2013 Elsevier B.V. All rights reserved.

Human natural killer (NK) cells are a subpopulation of lymphocytes that makes important contributions to innate immunity, adaptive immunity and reproduction. They originate from hematopoietic progenitors in the bone marrow and, in both physiological and pathological conditions, migrate in various tissues including secondary lymphoid organs (SLO) [1]. Two main subsets exist that are characterized by different surface phenotypes and functional properties. The majority of NK cells found in nonreactive lymph nodes and, with few exceptions, peripheral tissues are poor cytolytic (perforinlow ), IFN␥ producing CD56bright , CD16− cells, while in peripheral blood most NK cells are represented by cytolytic (perforinhigh ), IFN␥ producing CD56dull , CD16+ cells. The subsets are sequential stages of maturation and CD56bright can

夽 This work was supported by Investigator Grants (10643 and 11650) and special project 5×1000 (9962) from Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.), and by Ministero dell’Istruzione, dell’Università e della Ricerca (M.I.U.R). F. Bellora is recipient of a fellowship awarded by A.I.R.C. (special project 5×1000, 9962). We apologize to the colleagues whose work we could not cite because of space constraints. ∗ Corresponding author at: Istituto Giannina Gaslini, L.go G. Gaslini 5, 16147 Genova, Italy. Tel.: +39 010 3537886; fax: +39 010 3537576. E-mail address: [email protected] (C. Bottino).

progress to CD56dull cells also upon activation, as occurs in reactive lymph nodes or inflamed tissues [2]. Although the exact site(s) of NK cell maturation (bone marrow and/or SLO) is still debated, the process is accompanied by the expression of inhibitory surface receptors that recognize determinants of HLA class I molecules. CD56bright cells express CD94/NKG2A, which recognizes the non-polymorphic HLA-E molecules coupled with peptides from the leader sequences of classical HLA class I alleles [3]. CD56dull cells are an heterogeneous population that presents clonally distributed members of the inhibitory Killer Ig-like Receptors family (iKIR), potent immune tyrosine-based inhibitory motifs (ITIM) – bearing receptors that recognize polymorphic determinants of HLA-A, -B and -C alleles [4]. The inherited KIR genotype dictates the possible KIR phenotype of NK cells in a given individual and iKIR/self HLA class I interactions render NK cells tolerant to self, a process termed “NK cell licensing”, and allow them to become fully differentiated, armed cells during both development and immune responses [5]. Thus, when activated, licensed mature NK cells do not attack healthy selftissues while exerting a potent cytolytic activity against tumors or infected cells. With the exception of hematological malignances, most tumor cells down-regulate HLA class I, thus expressing “non protective” levels of ligands for the cognate inhibitory receptors. Importantly,

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Fig. 1. Tissue-specific chemokine expression patterns drive human NK cell subsets in both normal and pathological conditions. The two main human NK cell subsets display a different array of chemokine receptors. The ligands of these receptors (red boxes) are differently expressed in human organs and their expressions change following inflammation or neoplastic transformation of the tissue. This might account for the different distribution and trafficking of the two NK cell subsets in the indicated human body compartments (blue boxes), both at steady state and pathology.

Fig. 2. M1-polarizing stimuli can direct the M0 and M2 functional behavior toward NK-stimulatory capability. M0 (unpolarized) and M2 polarized macrophages following capture of microbial products, such as LPS and BCG, polarize toward M1 and induce strong activation of resting NK cells resulting expression of activation markers (CD69, CD25), in enhancement of anti-tumor cytotoxicity, release of IFN-␥ and expression of CCR7, a chemokine receptor crucial for their recruitment into SLO. NK-macrophage crosstalk also enhances the “editing” capability of NK cells, which become capable of killing M0, M2 and iDC.

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Fig. 3. A subset of M0 and M2 express a membrane-bound form of IL-18, which is released in small amounts after TLR engagement. M-CSF induces the expression of a membrane-bound form of IL-18 (mIL-18) in a subset of macrophages differentiating from both CD16− and CD16+ monocytes (Mo). While M2 polarization does not modify mIL-18 expression, M1 polarization induces CCR7 expression on macrophages and the protease(s)-mediated shedding of mIL-18. Soluble IL-18 (sIL-18) acts in close cell-to-cell contact and is crucial for CCR7 expression and IFN-␥ release by resting NK cells.

tumor transformation enhances the expression of molecules that are recognized by a large array of surface molecules that trigger NK cell function [6,7]. NK cells express an activating receptor complex built on immune tyrosine-based activating motifs (ITAM), which is composed by the NKp46, NKp30 and NKp44 receptors (collectively termed natural cytotoxicity receptors, NCR) linked to homoor hetero-dimers of CD3␨, Fc␧R␥ or DAP12 signaling molecules [8]. Moreover, co-stimulatory signals are provided by 2B4 [9], which is physically and functionally associated with the linker for activation of T cells (LAT) [10] and NTB-A [11], which require the binding with the signaling lymphocyte activation molecule-associated protein (SAP) to co-operate with NCR [11,12]. Moreover, NK cells express additional receptors that either directly transduce activating signals or use chains devoid of classical ITAM such as DNAM-1 and NKG2D/DAP10, respectively [6,7]. The cellular ligands of activating NK cell receptors include denovo expressed danger signals and molecules that are present in healthy cells but over-expressed upon cell transformation. DNAM-1 recognizes PVR and Nectin-2 [13], two members of the Nectin family, which are involved in cell-to-cell contacts, transendothelial migration and over-expressed in tumors of different histotype [14–16]. NKG2D interacts with MICA/B and ULBPs, MHC class I-related stress inducible molecules de-novo expressed after tumor transformation and virus infection [17]. The co-receptors recognize molecules whose expression is mostly restricted to hematopoietic cells and, in particular, 2B4 interacts with CD48 [18] and NTB-A displays homophilic recognition [19]. While viral glycoproteins have been identified that bind to NCR [20], their tumor ligands are not fully defined. B7-H6 and, very recently, a novel isoform of the mixed-lineage leukemia (MLL5) protein have been identified that bind to NKp30 and NKp44, respectively, and are expressed on a large panel of tumors [21–23].

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It is of note that, besides the cytolytic activity, NK cells have been shown to regulate both innate and adaptive immune responses by releasing chemokines (CCL3 and CCL5) and large amounts of T-helper (Th1) cytokines such as IFN-␥. Overall, mounting evidence demonstrates that NK cells, once activated, promote type 1 “tumor suppressing” responses and efficiently kill tumor cells by perforin-dependent delivery of pro-apoptotic granzymes [24]. Notably, NK cells would also kill cancer stem cells (CSC) [25–27], a highly malignant cancer subpopulation that would be crucial in tumor perpetuation, spreading and recurrence. Thus, NK cells are appealing candidates for innovative therapeutic protocols aimed at exploiting and increasing the function of anti-tumor immune responses in patients with hematological and non-hematological malignances. In hematopoietic stem cell transplantation (HSCT) NK cells are the first to reconstitute and would reach full maturation possibly as a consequence of a “licensing” process mediated by bystander hematopoietic cells present in the transplant. In haploidentical HSCT (haplo-HSCT), the iKIR/KIR ligand mismatch in the donor vs. recipient direction have revealed favorable effects in adults with acute myeloid leukemia (AML) and in children with high-risk acute lymphoblastic leukemia (ALL) [4,28]. In haplo-HSCT, donors’ NK cell subsets that express iKIRs that do not recognize HLA class I allotypes present in the recipient display strong alloreactivity, contribute to eradication of leukemic blasts (graft-versus-leukemia effect, GvL) and to the clearance of residual recipient’s DC and T lymphocytes, thus preventing graft-versus-host-disease (GvHD) and graft-rejection, respectively. Recently, an additional role in haplo-HSCT has been demonstrated for donor’s NK cell subsets expressing the activating KIRs (aKIR) that are engaged by HLA class I allotypes of the recipient [4]. Moreover, it has been shown that human cytomegalovirus (HCMV)

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reactivation after transplantation could be beneficial since it accelerates NK cell development and induces the expansion of NK cell populations expressing the activating CD94/NKG2C receptor, a typical HCMV-related signature [29,30]. These cells would contribute to both the control of HCMV infection after HSCT and reduction of leukemia relapse [31,32]. Thus, in hematological malignances in order to improve patients’ clinical outcome, the KIR and HLA class I genotype/phenotype must be taken into account since it allows to select the best “alloreactive” HSCT donor. Moreover, adoptive transfer of purified NK cells from the same donor could protect patients in the gap between HSCT and NK cell reconstitution/maturation (Killig M., submitted for publication). In this context, in haplo-hematopoietic transplant clinical benefits has been observed using a novel methodological approach based on the infusion of T- and B-depleted grafts, which are characterized by the presence of mature NK and ␥/␦ cells [4]. Unlike hematological malignances, the possible exploitation of NK cells in the treatment of solid tumors is still debated. In vitro experiments suggest that NK cells of patients could be able of recognizing autologous cancer cells even in advanced stage of the disease. In particular, in most cases the number and, when activated in vitro, the functional properties of peripheral blood NK cells of patients are comparable to those of healthy donors. However, clinical evidences demonstrate that in vivo the NK-mediated immune response does not occur or is poorly efficient and few cells are detectable within the tumor tissues. Most of the tumor-associated NK cells display an immature (CD56bright , CD16− ) or intermediate (CD56bright , CD16+ ) phenotype while cells displaying the typical signature of mature, armed NK cells (CD56dull , CD16+ , KIR+ ) are rarely detected [28,33] (Bellora F. et al., submitted for publication). In this context, CD56bright cells would display an improved survival under the oxidative stress condition that characterizes the tumor microenvironment [34]. Enrichment in immature, disarmed NK cells could be the result of a chemokine milieu that selectively recruit the CD56bright cell subset and/or the lack of a favorable environment for NK cell survival, maturation and/or activation. The chemokine receptor repertoire of NK cells together with the local chemokine milieu could play a crucial role in modifying the recruitment of the NK cell subsets in both healthy and tumor tissues (Carrega P et al., submitted for publication) (Fig. 1). CD56bright NK cells constitutively express CCR7 (CCL19, 21 receptor), which justify their selective presence in SLO [35], CCR5 (CCL3–5 receptor) and share CXCR4 (CXCL12 receptor) with CD56dim NK cell counterpart. CXCR3 (CXCL4, 9–11 receptor) is also shared between the two subsets although on CD56dim is generally expressed at lower levels. CD56bright and a subset of CD56dull cells also bind to high endothelial venules (HEV) thanks to the expression of CD62L [36]. The CD56dim cells mainly migrate to peripheral tissues due to the expression of CX3 CR1 (fractalkine receptor), CXCR4, CXCR2 (CXCL1–3, 5, 8 receptor) and CXCR1 (CXCL8 receptor), although, in the presence of IL-18, they can also express CCR7 [1,37]. Moreover, NK cells migrate in response to factors that do not belong to the chemokine superfamily such as chemerin and the sphingosine1phosphate (S1P) molecule [38,39]. It has been shown that tumor cells can affect the chemokine receptor repertoire of NK cells. In particular, neuroblastoma cells up-regulate in both NK cell subsets the expression of CXCR3 and CXCR4, which is essential for homing, development and maintenance of NK cells in stromal cell niches within the bone marrow (BM), while down-regulating that of CX3 CR1 in the CD56dim subset [16]. The phenomenon is mostly dependent on the release by tumor cells of the immunomodulatory cytokine TGF␤1, and rTGF␤1 (and rTGF␤2) induces in vitro a chemokine receptor repertoire similar to that detected in vivo in neoplastic patients. Notably, TGF␤1 also down-regulates the expression of NKp30 and NKG2D

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activating NK receptors [16] and induces in NK cells the release of factors such as the vascular endothelial growth factor (VEGF) [40], a pro-angiogenic phenotype that in physiological conditions is restricted to decidual natural killer (dNK) cells [41]. An altered NK cell recruitment could match with defective cytolytic NK cell functions in either infected or tumor tissues. A combination of immunostimulatory, innate or adaptive cytokines such as IL-15, IL-12, IL-18 and IL-2 as well as cell-to-cell contacts are needed to induce NK cell maturation, survival as well as activation, which renders these cells efficient killers [42]. In this context, within the tumor microenvironment, NK cells would meet up with not only neoplastic targets but also with other immune effectors such as T cells, dendritic cells (DC) and macrophages (M). It is known that the tumor microenvironment modifies the functional program of immune effectors toward an immunomodulatory, tumor-promoting phenotype. For example, tumor and stromal cells produce chemokines such as CCL2 that recruits monocytes from peripheral blood. However, once in tissue, the tumor microenvironment would prevent their differentiation into dendritic cells (DC) while promoting that into M. Moreover, it would twist the M polarization toward a pro-angiogenic/immunoregulatory “M2-like” phenotype with tumor promoting properties. The “alternative” M2 pathway of activation is characterized by reduced Ag presentation capabilities (MHClow ), high expression of scavenger receptors, iron release (ferropontinhigh ), fibroblast activation and collagen deposition (ArgIhigh ), release of matrix metalloproteinases (MMPs) and pro-angiogenic factors such as VEGF as well as of immunoregulatory cytokines (IL-10, TGF␤1) and chemokines (CCL17, CCL22 and CCL24), which dampen immune responses and recruit Th2 and Treg cells [43,44]. Notably, most studies have established a correlation between high numbers of tumor-associated macrophages (TAM) within a tumor and poor prognosis. Thus, in vivo, after recruitment into tumor tissues in response to appropriate chemokine gradients, NK cells would deal with “tumor-educated” immune cell types such as TAM that may counteract their anticancer activity. M polarizing toward M1 following capture of microbial products release immunostimulatory cytokines (IL-12, IL-18) and induce a strong activation of autologous NK cells, resulting in up-regulation of CD69 and CD25 activation markers, expression of CCR7, potentiation of anti-tumor cytolytic activity and release of type 1 cytokines such as IFN-␥. On the contrary, M2 polarized macrophages are unable to induce NK cell activation. However, microbial products can rescue M2 macrophages from the immunomodulatory condition and shape their function toward the M1-like, NK-stimulatory status [45]. During NK/M crosstalk, NKp46 plays a major role in killing of macrophages, DNAM-1 plays a dual role being involved in the induction of both cytolytic activity and IFN-␥ production while 2B4 is primarily involved in the induction of IFN-␥ [45]. Interestingly, a subset (30–40%) of unpolarized (M0) and M2 cells express a membrane bound form of IL-18 (mIL-18) that is released upon TLR stimulation (Fig. 3). Soluble IL-18 (sIL-18) by acting in close cell-to-cell contact promotes in NK cells both IFN-␥ release and expression of CCR7 [46], whose ligands are released by lymphatic vessel endothelium and secondary lymphoid organ stroma, therefore facilitating NK cell migration toward loco regional lymph nodes. It is of note that after exposure to microbial products, macrophages enter into a transient unresponsive state (“endotoxin tolerance”), a feedback mechanism that prevents over-exuberant inflammation and protect the host against endotoxin shock. Endotoxin tolerant macrophages present a gene reprogramming toward an M2-like functional phenotype, which includes increased expression of anti-inflammatory cytokines (IL10, TGF-␤, IL-1R␣) and reduced expression of pro-inflammatory ones. Endotoxin tolerant M do not express mIL-18, release negligible amounts of cytokines such as sIL-18 and IL-12 and are unable

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to activate resting NK cells [45]. Lack of NK cell activation could result in drop of IFN-␥ production, a further mechanism that prevents excessive inflammatory responses. Notably, once activated NK cells kill autologous (HLA Class Ilow ) M0, M2 and immature DC, while M1 and mature DC are spared because of the expression of “protective” high amounts of HLA class I molecules (Fig. 2). Thus, when appropriately stimulated, NK cells are able to select M and DC suitable for optimal “tumorsuppressive” type I responses (a process termed “editing”) as well as to reduce the number of “tumor promoting” M2 macrophages [45,47]. The data on the cross-talk between NK and in vitro derived M2 were confirmed using TAM from ascites of ovarian cancer patients, which display a reversible M2-like phenotype and are characterized by a remarkably high frequency/density of mIL-18 (Bellora F. et al., submitted for publication). Interestingly, NK cells would also interact and accelerate the apoptosis of neutrophils [48], a leukocyte subset that, similar to macrophages, can exert either anti-tumorigenic (N1) or protumorigenic (N2) function [49]. Finally, depending on the cytokine microenvironment (IL-12 or IL-4) NK cells themselves can be polarized into NK1 and NK2, which produce predominantly IFN-␥ and IL-5/IL-13, respectively [50]. Altogether, mounting evidence suggests the existence of a complex tumor microenvironment that would set up different rules to impair the attack of NK cells. This suggests the requirement of integrated biological strategies to restore and/or increase the anti-tumor capabilities of NK cells in neoplastic patients.

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Please cite this article in press as: http://dx.doi.org/10.1016/j.imlet.2013.12.009

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[47]

[48]

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Human

NK

cells

and

NK

receptors.

Immunol

Lett

(2013),

Human NK cells and NK receptors.

In early seventies "natural killer (NK) cells", a third lymphocyte subset was discovered that revealed an unexpected ability to kill syngeneic and all...
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