Natural killer cells: role in local tumor growth and metastasis

Figures & data

Figure 1 Electron micrographics of natural killer (A) and NK-92 (B) cells showing large lymphocyte-containing granules (arrows).

Note: Scale bar, 2 μm.
Abbreviation: N, nucleus.

Figure 2 Recognition mechanisms of target cells by NK cells: “missing and induced self” theory. NK cell response is not initiated if neither ligands for NK-activating receptors nor MHC-I are expressed on target cells (A). If inhibitory receptors interact with MHC-I molecules without ligands for activating receptors no cytotoxicity is observed (B), whereas engagement of these receptors in absence of MHC-I molecule induced a strong NK cell response (C). In most cases, NK cell response depends on a balance between inhibitory and activating receptor signaling (D). Normal cells are protected against NK cell cytotoxicity because they usually express MHC-I molecules and no or low level of activating receptor ligands.

Notes: In contrast, cell transformation could induce a down-modulation of MHC-I molecules and/or an overexpression of ligands for activating receptors resulting in NK cell recognition and tumor cell lysis.
Abbreviations: MHC-I: major histocompatibility complex class I; NK, natural killer.

Figure 3 Human natural killer cell subsets based on CD56 and CD16 expressions: Around 90% of natural killer cells isolated from the blood display dim level of CD56 and high density of CD16 (CD56^dimCD16^bright).

Notes: These cells are more cytotoxic via perforin and granzyme secretion¹⁵ than natural killer cells showing bright expression of CD56 and no or low expression of CD16 (CD56^brightCD16^−/low). These latter cells produce more cytokines.¹⁶
Abbreviations: GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN-γ, interferon γ; IL-10, interleukin 10; TNF-α, tumor necrosis factor α.

Table 1 Main receptors on NK cells involved in anti-tumor immune response

Function	Receptors	Ligands	Species	Ref
Inhibition	KIR (long cytoplasmic tail)	HLA-A,B,C allotypes	H	^Citation42,Citation43
	Ly49A/C	MHC class I	M	^Citation44,Citation45
	CD94-NKG2A	MHC-E	H, M	^Citation48,Citation50
Activation	CD16	IgG	H, M
		HPV	H	^Citation61
	NKG2D	MICA/B-RAET	H
		RAET-H60	M
	NKp30	B7-H6, Heparan sulfate	H	^Citation75^–^Citation78
	NKp44	Heparan sulfate	H	^Citation76
	NKp46	Heparan sulfate, unknown tumor ligands	H, M	^Citation75,Citation76,Citation121

Abbreviations: HLA, human leucocyte antigen; H, Human; Ig, immunoglobulin; M, mouse; MHC, major histocompatibility complex; MICA/B, major histocompatibility complex class I-related; RAET, retinoic acid early transcript.

Figure 4 Overview of NK cell responses against tumor cell.

Abbreviations: NK, natural killer; DC, dendritic cell; IFN-γ, interferon γ; IL, interleukin; KIR, killer-cell immunoglobulin-like receptor; mAb, monoclonal antibody; NCR, natural cytotoxicity receptor; TNF-α, tumor necrosis factor α.

NaglerALanierLLCwirlaSPhillipsJHComparative studies of human FcRIII-positive and negative natural killer cellsJ Immunol198914310318331912530273

 PubMed Web of Science ®Google Scholar

CooperMAFehnigerTATurnerSCHuman natural killer cells: a unique innate immunoregulatory role for the CD56(bright) subsetBlood200197103146315111342442

 PubMed Web of Science ®Google Scholar

AdamCKingSAllgeierTDC-NK cell cross talk as a novel CD4+ T-cell-independent pathway for antitumor CTL inductionBlood2005106133834415769894

 PubMed Web of Science ®Google Scholar

JacobsNBoniverJHubertPDelvennePDendritic cells: more than just adaptive immunity inducers?Curr Immunol Rev200731722

 Google Scholar

LjunggrenHGKärreKHost resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanismJ Exp Med19851626174517593877776

 PubMed Web of Science ®Google Scholar

FrankssonLGeorgeEPowisSButcherGHowardJKärreKTumorigenicity conferred to lymphoma mutant by major histocompatibility complex-encoded transporter geneJ Exp Med199317712012058418201

 PubMed Web of Science ®Google Scholar

JamilKMKhakooSIKIR/HLA interactions and pathogen immunityJ Biomed Biotechnol2011201129834821629750

 PubMedGoogle Scholar

OrrMTLanierLLInhibitory Ly49 receptors on mouse natural killer cellsCurr Top Microbiol Immunol2011350678720680808

 PubMed Web of Science ®Google Scholar

LanierLLCorlissBCWuJLeongCPhillipsJHImmunoreceptor DAP12 bearing a tyrosine-based activation motif is involved in activating NK cellsNature199839166687037079490415

 PubMed Web of Science ®Google Scholar

CostelloRTSivoriSMarcenaroEDefective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemiaBlood200299103661366711986221

 PubMed Web of Science ®Google Scholar

VitaleMBottinoCSivoriSNKp44, a novel triggering surface molecule specifically expressed by activated natural killer cells, is involved in non-major histocompatibility complex-restricted tumor cell lysisJ Exp Med199818712206520729625766

 PubMed Web of Science ®Google Scholar

PessinoASivoriSBottinoCMolecular cloning of NKp46: a novel member of the immunoglobulin superfamily involved in triggering of natural cytotoxicityJ Exp Med199818859539609730896

 PubMed Web of Science ®Google Scholar

ShiFDLjunggrenHGSarvetnickNInnate immunity and autoimmunity: from self-protection to self-destructionTrends Immunol20012229710111286711

 PubMed Web of Science ®Google Scholar