Roshan Zamir Mina, Ariafar Ali, Ghaderi Abbas, Amirzargar Aliakbar
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Urology-Oncology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Urology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Immunobiology. 2023 Mar;228(2):152319. doi: 10.1016/j.imbio.2022.152319. Epub 2022 Dec 27.
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 Bw4 (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-Bw4 (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 Bw4, 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.
自然杀伤（NK）细胞的发育很大程度上依赖于杀伤细胞免疫球蛋白样受体（KIR）和人类白细胞抗原（HLA）I类配体。在本研究中，我们调查了KIR基因、HLA配体以及KIR - HLA组合在前列腺癌（PC）易感性或防护中的作用。为分析16个KIR基因和5种HLA配体的频率，我们对150例PC患者和200例健康对照（CNs）进行了序列特异性引物聚合酶链反应（PCR - SSP）。与对照组相比，PC患者中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 Bw4（p = 0.0401，OR = 0.35552，CI = 0.1466 - 0.9059）、HLA Bw4（p = 0.0190，OR = 0.4744，CI = 0.2656 - 0.8521）以及T4基因簇（包括KIR2DS5 - 2DL5 - 3DS1 - 2DS1基因）（p = 0.0194，OR = 0.5575，CI = 0.3449 - 0.8938）的频率较低。此外，与CNs相比，PC患者中激活型KIR（aKIR）>抑制型KIR（iKIR）的基因型频率较低（p = 0.0298，OR = 0.5291，CI = 0.3056 - 0.9174），以及iKIR + HLA < aKIR + HLA的频率较低（p = 0.0183，OR = 0.2197，CI = 0.0672 - 0.7001），这意味着aKIR基因具有保护作用。在KIR - HLA相互作用方面，我们检测到KIR3DS1 + HLA - A Bw4（p = 0.0113，OR = 0.5093，CI = 0.3124 - 0.8416）和KIR3DL1 + HLA - A Bw4（p = 0.0306，OR = 0.1153，CI = 0.0106 - 0.6537）组合与前列腺癌抗性之间存在显著关联。相反，在不存在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）和HLA - Bw4（p = 0.0071，OR = 2.505，CI = 1.319 - 4.703）基因的情况下存在KIR3DL1可能易患前列腺癌。PC患者携带CxT4基因型与较低的肿瘤分级（Gleason评分≤6）呈正相关（p = 0.0331，OR = 3.290，CI = 1.181 - 8.395）。总之，我们的数据表明aKIRs、HLA - B Bw4和HLA Bw4配体具有保护作用，以及某些KIR - HLA组合在前列腺癌中具有易患作用。本研究结果为男性前列腺癌人群风险评估提供了新的见解。此外，基于KIR - HLA组合预测免疫治疗反应有助于在疾病早期实施最有效的治疗方法。
