Anti-natural Killer Inhibitory Receptors in Elderly Patients with Acute Myeloid Leukaemia
or antigens recognised by the adaptive immunity. Most innate immunity effectors including T gamma delta, NK and monocytes play an anticancer role. NK cells have been extensively analysed in AML and chronic myeloid leukaemia (CML).
Different NK cell subsets can efficiently lyse target cells or produce cytokines and chemokines in the absence of prior stimulation. A hypothesis called ‘the missing self-hypothesis’ predicts that NK cells will be no more inhibited and lyse target cells when expression of major histocompatibility complex (MHC) class I is lost or deficient on the target cells. Human NK cells have inhibitory receptors that recognise MHC class I molecules as their cognate ligands on virtually every cell in the body. These receptors include the inhibitory KIRs that bind to classical MHC class Ia ligands (human leukocyte antigen [HLA]-A, B and C) (see Table 1) and the inhibitory CD94-NKG2A heterodimeric receptors that bind the non-classic MHC class Ib (HLA- E). Another inhibitory NK receptor is the C-type lectin-like receptor NKR-P1A (CD161) that interacts with lectin-like transcript-1, a host- encoded non-MHC ligand. NK cells also express activating receptors such as the natural cytotoxicity receptors (NCRs) NKp30, NKp44 and NKp46. NK cell function is thus governed by both inhibitory and activating surface receptors.
It has been shown that NK cells can lyse the different subtypes of leukaemia or leukaemic cell lines, but the mechanisms underlying the interaction and destruction of these cells are not clearly defined (see Figure 1).
In AML patients, NK cell activity correlates positively with relapse-free survival, which suggests that NK cells may play an important role in the control and clearance of leukaemia.12
On the other hand, the
and abnormalities of NK cell phenotype or activity during leukaemia have recently been identified.14
activity of autologous NK cells against leukaemic cells is frequently reduced13
A variety of escape
mechanisms to the immune system and especially NK cells have been found in AML patients and are described below.
Deficient HLA class I expression (reduced expression or loss of HLA class I alleles) has been described in malignant cells. HLA class I molecules belonging to the Bw6 group were more frequently downregulated than those belonging to the HLA-Bw4 group.16
Inhibitory Receptors and Acute Myeloid Leukaemia
There is a dominance of inhibitory over-activating signals in leukaemic patients.15
However,
until now the expression of the ligands for KIR2DL4 and NKG2A, namely HLA-G or HLA-E, has not been demonstrated on leukaemic cells.16
Activatory Receptors and Acute Myeloid Leukaemia
Defective cytotoxicity of AML cells can be explained by abnormalities of activating NK receptor expression.14 mediate NK-dependent leukaemia cell lysis.17,18
0
MICA/B ULBP1 ULBP2 ULBP3 PVR NECTIN 2 9 AML
The putative NCR ligands that are expressed during the maturation of normal myelo-monocytic cells have weak expression on AML blasts.21 The expression of NKG2D ligands by leukaemic cells has been observed by Salih et al.,22
but not by Pende et al.23
expression of NKG2D ligands on AML blasts at diagnosis but only on AML of M4 and M5 subtypes24
Table 1: Killer Inhibitory Receptors
KIR CD
2DL1 CD158A Strong 2DL2 CD158B1 Strong 2DL3 CD158B2 Weak
2DL4 CD158D 2DL5 CD158F 2DS1 CD158H 2DS2 CD158J 2DS3 No CD 2DS4 CD158I 2DS5 CD158G 3DL1 CD158E1
3DL2 CD158K 3DL3
3DS1 CD158E2 None None
Arginine None
Lysine Lysine Lysine Lysine Lysine None
None None
Lysine
Inhibition Charged TMaa Ligand
None
HLA-Clys80 C2 (HLA- Cw2/4/5/6/15/17)
HLA-CAsn80 C1 (HLA- Cw1/3/7/8/12,13,14)
HLA-CAsn80 C1(HLA- Cw1/3/7/8/12/13/14) HLA-G, A3, B46 ?
HLA-Clys80 C2 HLA-CAsn80 C1? ? ? ?
HLA-Bw4(B51/52/53/57/ 58/13/27/37/44 A24) HLA-A3,A11 ?
HLA-Bw4?
HLA = human leukocyte antigen; KIR = killer inhibitory receptors.
Figure 1: Interaction Between NK Cells and Primary Acute Myeloid Leukaemia Blasts
100
20 40 60 80
A recent study has showed the (see Figure 2). Finally, recent studies have
This central role for DNAM-1 is confirmed by monoclonal antibody (mAb)-mediated blocking experiments.17
In vitro data show that NCRs We have demonstrated
that the majority of NK cells in AML patients display an abnormal phenotype characterised by a downregulation of NKp30 and NKp46 NCR that correlates with a defective cytolytic function against autologous AML cells (NCR-dull).18
Interestingly, the NCR surface
density is restored completely (NKp46) or partially (NKp30) when a complete remission is obtained with chemotherapy.19
In addition,
there is defective killing of dendritic cells by autologous NK cells from AML patients, which may contribute to leukaemia escape.20
Finally, a
correlation between the downregulation of NCR and shorter survival was seen in AML patients.19
EUROPEAN ONCOLOGY
What Has Haematopoietic Stem Cell Transplantation Taught Us Regarding Interactions Between Allogeneic NK and Acute Myeloid Leukaemia?
Both murine and human studies show that NK cells mediate a number of potentially beneficial functions following allo-HSCT, including eliminating residual malignant cells (the graft-versus-leukaemia [GvL]
87
In vivo, the activity of NK cells against AML blasts has been shown in a mice xenograft model.25
NK cells can recognise, be activated by and eventually kill AML blasts in vitro and in vivo and that AML blasts alter NK functions in vivo.
Altogether, these data demonstrate that
demonstrated significant expression for PVR and Nectin-2, the ligands of the DNAX accessory molecule-1 (DNAM-1 or CD226) on leukaemic cells.17
Percentage
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