The impact of killer cell immunoglobulin-like receptor (KIR) genes and human leukocyte antigen (HLA) class I ligands on predisposition or protection against prostate cancer

Abstract

Natural killer (NK) cell development largely depends on killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands. In the current study, we investigated the role of KIR genes, HLA ligands, and KIR-HLA combinations in vulnerability or protection against prostate cancer (PC). To analyze the frequency of 16 KIR genes and 5 HLA ligands, polymerase chain reaction with sequence-specific primers (PCR-SSP) was conducted in 150 PC patients and 200 healthy controls (CNs). KIR2DL5 (p = 0.0346, OR = 0.606, CI = 0.3916–0.9336), KIR2DS5 (p = 0.0227, OR = 0.587, CI = 0.3793–0.9139), HLA-B Bw4Thr80 (p = 0.0401, OR = 0.3552, CI = 0.1466–0.9059), HLA Bw4 (p = 0.0190, OR = 0.4744, CI = 0.2656–0.8521), and T4 gene cluster (including KIR2DS5-2DL5-3DS1-2DS1 genes) (p = 0.0194, OR = 0.5575, CI = 0.3449–0.8938) had a lower frequency in the PC patients compared to the control group. Moreover, a lower frequency of the genotypes contacting activating KIR (aKIR) > inhibitory KIR (iKIR) (p = 0.0298, OR = 0.5291, CI = 0.3056–0.9174) and iKIR + HLA < aKIR + HLA (p = 0.0183, OR = 0.2197, CI = 0.0672–0.7001) in PC patients compared to the CNs implies a protective role for aKIR genes. In the case of KIR-HLA interactions, we detected a significant association between KIR3DS1+ + HLA-A Bw4+ (p = 0.0113, OR = 0.5093, CI = 0.3124–0.8416) and KIR3DL1− + HLA-A Bw4+ (p = 0.0306, OR = 0.1153, CI = 0.0106–0.6537) combinations and resistance to prostate cancer. In contrast, the presence of KIR3DL1 in the absence of HLA-A Bw4 (p = 0.0040, OR = 2.00, CI = 1.264–3.111), HLA Bw4 (p = 0.0296, OR = 2.066, CI = 1.094–3.906), and HLA-Bw4Thr80 (p = 0.0071, OR = 2.505, CI = 1.319–4.703) genes probably predisposes to prostate cancer. Carrying the CxT4 genotype in PC patients was positively associated with lower tumor grades (Gleason score ≤ 6) (p = 0.0331, OR = 3.290, and CI = 1.181–8.395). Altogether, our data suggest a protective role for aKIRs, HLA-B Bw4Thr80, and HLA Bw4 ligands as well as a predisposing role for certain KIR-HLA combinations in prostate cancer. The findings of this study offer new insight into the population's risk assessment for prostate cancer in men. Additionally, predicting immunotherapy response based on KIR-HLA combinations aids in implementing the most effective therapeutic approach in the early stages of the disease.