Coexistence of inhibitory and activating killer-cell immunoglobulin-like receptors to the same cognate HLA-C2 and Bw4 ligands confer breast cancer risk

Karan Rajalingam,Raja Rajalingam,Elham Ashouri,Shirin Farjadian,Shaghik Barani,Abbas Ghaderi

doi:10.1038/s41598-021-86964-y

Abstract

Human leukocyte antigen (HLA) class I-specific killer-cell immunoglobulin-like receptors (KIR) regulate natural killer (NK) cell function in eliminating malignancy. Breast cancer (BC) patients exhibit reduced NK-cytotoxicity in peripheral blood. To test the hypothesis that certain KIR-HLA combinations impairing NK-cytotoxicity predispose to BC risk, we analyzed KIR and HLA polymorphisms in 162 women with BC and 278 controls. KIR-Bx genotypes increased significantly in BC than controls (83.3% vs. 71.9%, OR 1.95), and the increase was more pronounced in advanced-cancer (OR 5.3). No difference was observed with inhibitory KIR (iKIR) and HLA-ligand combinations. The activating KIR (aKIR) and HLA-ligand combinations, 2DS1 + C2 (OR 2.98) and 3DS1 + Bw4 (OR 2.6), were significantly increased in advanced-BC. All patients with advanced-cancer carrying 2DS1 + C2 or 3DS1 + Bw4 also have their iKIR counterparts 2DL1 and 3DL1, respectively. Contrarily, the 2DL1 + C2 and 3DL1 + Bw4 pairs without their aKIR counterparts are significantly higher in controls. These data suggest that NK cells expressing iKIR to the cognate HLA-ligands in the absence of putative aKIR counterpart are instrumental in antitumor response. These data provide a new framework for improving the utility of genetic risk scores for individualized surveillance.

Highlights

Human leukocyte antigen (HLA) class I-specific killer-cell immunoglobulin-like receptors (KIR) regulate natural killer (NK) cell function in eliminating malignancy
Genes are involved in the risk of breast cancer, we determined the presence and absence of all 16 KIR genes and cognate HLA class I ligands in 162 patients with breast cancer and 278 healthy controls from the native population of southern Iran
Sixty-one KIR genotypes were encountered in patients with breast cancer, while only 49 KIR genotypes were found in controls

Summary

Introduction

Human leukocyte antigen (HLA) class I-specific killer-cell immunoglobulin-like receptors (KIR) regulate natural killer (NK) cell function in eliminating malignancy. The 2DL1 + C2 and 3DL1 + Bw4 pairs without their aKIR counterparts are significantly higher in controls These data suggest that NK cells expressing iKIR to the cognate HLA-ligands in the absence of putative aKIR counterpart are instrumental in antitumor response. In addition to framework genes, group A haplotypes have a fixed set of four genes (KIR2DL3-2DL1-3DL1-2DS4) and encode inhibitory KIRs, 2DL1, 2DL3, 3DL1, and 3DL2, specific for all four HLA class I ligands, C2, C1, Bw4, and A3/A11 respectively. Certain activating KIRs display a high degree of sequence homology with the corresponding inhibitory KIR in their extracellular Ig domains. These activating KIRs are expected to exhibit a binding specificity similar to their inhibitory counterpart. The activating KIR2DS3 was not demonstrated to bind any HLA24,25

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