Genetic polymorphism of NK receptors and their ligands in melanoma patients: prevalence of inhibitory over activating signals

Abstract

Antitumor cytotoxicity of NK cells and T cells expressing NK-associated receptors is regulated by interaction between their cell surface killer immunoglobulin-like receptors (KIRs) and CD94/NKG2 heterodimers with MHC class I ligands on target cells. To test the hypothesis that KIR and/or HLA polymorphisms, and KIR/HLA combinations could contribute to the tumorigenesis, association studies were performed in 50 patients with malignant melanoma (MM) in different stages of disease and 54 controls. Our data showed that the frequency of inhibitory and activating KIR genes and KIR genotypes did not differ significantly between healthy individuals and melanoma patients. HLA haplotype distribution showed statistically significant increased frequencies of A*01-B*35-Cw*04 (0.069 vs 0.000; pc < 0.05; OR = 19.9), A*01-B*08-DRB1*03 (0.079 vs 0.019; pc < 0.05; OR = 4.5), and A*24-B*40-DRB1*11 (0.026 vs 0.000; pc < 0.05; OR = 7.1) in melanoma patients compared with healthy controls. Individuals homozygous for group 2 HLA-C ligands were less frequent in the patient group compared with the control cohort (12% vs 31.5%; p < 0.017). In addition, we observed an increased frequency (88.0% vs 68.5%; p = 0.017; OR = 2.80) of KIR2DL2/2DL3 in combination with their group 1 HLA-C ligands, while the presence of these KIRs in the absence of the putative ligands was decreased (12.0% vs 31.5%; p = 0.017) in the patient group. Furthermore, an increased frequency of activating KIR2DS1 in the absence of the putative HLA-C(Lys80) ligands was found in melanoma patients (16.0% vs 9.2%). In contrast, KIR2DS2 was absent in patients more often (38.0% vs 25.9%) when the presumptive HLA-C(Asn80) ligands were present. A slightly higher incidence of KIR3DL1 in combination with the less effective Bw4(Thr80) ligands was seen in patients with primary (20.8%) compared with metastatic (4.2%) disease. The data obtained in this study imply that there may not be a direct association between KIR gene content in the genome and the presence of malignant melanoma, or melanoma progression. However, some HLA haplotypes could be predisposing to MM in the Bulgarian population. Furthermore, distinct KIR/HLA ligand combinations may be relevant to the development of malignancy whereby inhibition overrides activation of NK cells and T cells expressing NK-associated receptors, which in turn might facilitate tumor escape and progression.

Susceptibility to myeloid and lymphoid leukemia is mediated by distinct inhibitory KIR-HLA ligand interactions

“…Consistent with our finding, a recent study showed that the presence of inhibitory KIR2DL2/2DL3 in association with their putative ligands was also increased in melanoma patients compared to healthy individuals. 7 Finally, we also found that 27.1% of patients who were heterozygous for KIR2DL2/2DL3 were also heterozygous for HLA-C1/C2 (versus 12.8% in the control group, P ¼ 0.020) (data not shown).…”

Receptor systems controlling natural killer cell function are genetically stratified in Europe

“…52 PCR-SSOP was carried out to confirm the presence or absence of KIR genes in Northern and Republic of Ireland populations as previously described. KIR gene and genotype frequencies of an additional 36 global population (4218 individuals from 38 different studies) were obtained from the published literature (35 populations [31][32][33]46,48,49,[53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] ) and from an online database www.allelefrequencies.net. 72 Genotypes were classified as follows: the absence of 2DL2, 2DL5, 3DS1, 2DS1, 2DS2, 2DS3 or 2DS5 indicates that an individual is homozygous for the A genotype (that is, AA).…”

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals

“…11,12 KIRs are key receptors of human natural killer (NK) cells, a subset of lymphocytes that trigger early immune response against infection and tumors, while maintaining tolerance to healthy self. 13,14 Further, CD8 þ cytotoxic T lymphocytes (CTL) with memory phenotype and CD4 þ CD28 null T cells also express KIRs indicating KIRs' regulatory role in antigen-specific adaptive immunity.…”