Romero J M, Aptsiauri N, Vazquez F, Cozar J M, Canton J, Cabrera T, Tallada M, Garrido F, Ruiz-Cabello F
Servicio de Analisis Clinicos, Hospital Universitario Virgen de las Nieves, University of Granada, Avenida de las Fuerzas Armadas s/n, 18014 Granada, Spain.
Tissue Antigens. 2006 Oct;68(4):303-10. doi: 10.1111/j.1399-0039.2006.00673.x.
Changes in the human leukocyte antigen (HLA) class I expression and cytokine and chemokine production both by cancer cells and by normal surrounding tissue are believed to be responsible for immune escape and tumor progression. In this study, we compared the tumor expression levels of HLA heavy chain (HLAhc), beta-2-microglobulin (beta2m), chemokines (Interferon-gamma-inducible Protein-10 (IP-10), Interferon-inducible T-cell Alpha-Chemoattractant (I-TAC), Stromal cell-Derived Factor-1 (SDF-1), Macrophage Inflammatory Protein-1-alpha (MIP-1-alpha) and Regulated upon Activation, Normally T-Expressed, and presumably Secreted (RANTES)) and cytokines (Vascular Endothelial Growth Factor (VEGF), Interferon-gamma (IFN-gamma), Interleukin-10 (IL-10), Tumor Growth Factor-beta (TGB-beta)) in primary tumors and adjacent normal tissues from patients with localized and metastatic renal cell carcinoma (RCC) using a quantitative real-time polymerase chain reaction technique. We report that the expression of HLAhc, beta2m and the studied cytokines and chemokines (except for SDF-1) was significantly higher in the tumor (29 samples) than in the normal tissue (14 samples). When we compared the tumor expression levels between patients with localized RCC and patients with advanced metastatic stage, we found that the messenger RNA expression levels of HLAhc and beta2m were much lower in patients with metastatic RCC (6 cases) than in patients with localized cancer (23 cases), with levels similar to those in normal tissue. This was also confirmed on a protein level by immunohistological labeling of tumor tissues. Thirty-nine percent of the analyzed RCC tumors showed partial loss of HLA class I molecules, while 6% of the tumors showed HLA class I total loss. The expression of IP-10, SDF-1 and VEGF-c was also significantly lower in patients with advanced tumor, while the IFN-gamma expression in metastatic RCC was not detectable. Our findings show that primary RCC tumors are characterized by a high expression of HLAhc and a presence of proinflammatory mediators and chemokines. We also observed that disease progression and development of metastasis in RCC are associated with decreased expression of HLAhc, beta2m, IP-10, SDF-1 and IFN-gamma. This microenvironment may suppress the cytotoxic response, creating conditions that favor tumor escape and cancer progression.
癌细胞和周围正常组织中人类白细胞抗原（HLA）I类表达以及细胞因子和趋化因子产生的变化被认为是免疫逃逸和肿瘤进展的原因。在本研究中，我们使用定量实时聚合酶链反应技术比较了局限性和转移性肾细胞癌（RCC）患者原发性肿瘤和相邻正常组织中HLA重链（HLAhc）、β2微球蛋白（β2m）、趋化因子（γ干扰素诱导蛋白10（IP-10）、干扰素诱导T细胞α趋化因子（I-TAC）、基质细胞衍生因子1（SDF-1）、巨噬细胞炎性蛋白1α（MIP-1α）和活化后正常T细胞表达并可能分泌的调节因子（RANTES））和细胞因子（血管内皮生长因子（VEGF）、γ干扰素（IFN-γ）、白细胞介素10（IL-10）、肿瘤生长因子β（TGF-β））的肿瘤表达水平。我们报告，肿瘤（29个样本）中HLAhc、β2m以及所研究的细胞因子和趋化因子（SDF-1除外）的表达明显高于正常组织（14个样本）。当我们比较局限性RCC患者和晚期转移阶段患者的肿瘤表达水平时，我们发现转移性RCC患者（6例）中HLAhc和β2m的信使RNA表达水平远低于局限性癌症患者（23例），其水平与正常组织相似。肿瘤组织的免疫组织学标记在蛋白质水平上也证实了这一点。39%的分析RCC肿瘤显示HLA I类分子部分缺失，而6%的肿瘤显示HLA I类分子完全缺失。晚期肿瘤患者中IP-10、SDF-1和VEGF-c的表达也明显较低，而转移性RCC中未检测到IFN-γ表达。我们的研究结果表明，原发性RCC肿瘤的特征是HLAhc高表达以及存在促炎介质和趋化因子。我们还观察到RCC疾病进展和转移的发生与HLAhcβ2m、IP-10、SDF-1和IFN-γ表达降低有关。这种微环境可能会抑制细胞毒性反应，创造有利于肿瘤逃逸和癌症进展的条件。
