Interleukin-10 Haplotype May Predict Survival and Relapse in Resected Non-Small Cell Lung Cancer

IL-10 is associated with tumor malignancy via immune escape. We hypothesized that IL-10 haplotypes categorized by IL-10 promoter polymorphisms at –1082A>G, –819C>T, and –592C>A might influence IL-10 expression and give rise to non-small cell lung cancer (NSCLC) patients with poor outcomes and relapse. We collected adjacent normal tissues from 385 NSCLC patients to determine IL-10 haplotypes by direct sequencing and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Of the 385 tumors, 241 were available to evaluate IL-10 mRNA expression levels by real-time RT-PCR. The influence of IL-10 haplotypes on overall survival (OS) and relapse free survival (RFS) were determined by Kaplan-Meier and multivariate Cox regression analysis. The results showed that IL-10 mRNA levels were significantly higher in tumors with the non-ATA haplotype than with the ATA haplotype (P = 0.004). Patients with the non-ATA haplotype had shorter OS and RFS periods than did patients with the ATA haplotype. This may be associated with the observation that the number of tumor-infiltrating lymphocytes was decreased in the tumors with higher levels of IL-10. Consistently, T cells from the peripheral blood of the patients with non-ATA haplotype were more susceptible to apoptosis and less cytotoxic to tumor cells, compared to those from the patients with ATA haplotype. The results suggest that IL-10 can promote tumor malignancy via promoting T cell apoptosis and tumor cell survival, and IL-10 haplotype evaluated by PCR-RFLP or direct sequencing may be used to predict survival and relapse in resected NSCLC, helping clinicians to make appropriate decisions on treatment of the patients.白细胞介素10（IL-10）可通过免疫逃逸参与肿瘤恶性进程。本研究提出如下假设：以IL-10启动子区域–1082A>G、–819C>T及–592C>A多态性位点分型的IL-10单倍型，可能影响IL-10的表达，进而导致非小细胞肺癌（NSCLC）患者预后不良并出现复发。本研究收集了385例NSCLC患者的癌旁正常组织，采用直接测序法与聚合酶链反应-限制性片段长度多态性（PCR-RFLP）对IL-10单倍型进行分型鉴定；在385例肿瘤样本中，241例可通过实时逆转录聚合酶链反应（real-time RT-PCR）检测IL-10 mRNA的表达水平。采用卡普兰-迈耶法与多因素Cox回归分析，评估IL-10单倍型对患者总生存期（OS）及无复发生存期（RFS）的影响。结果显示，携带非ATA单倍型的肿瘤组织中IL-10 mRNA水平显著高于ATA单倍型携带者（P=0.004）。非ATA单倍型患者的总生存期与无复发生存期均短于ATA单倍型患者。这一现象可能与高IL-10表达的肿瘤组织中肿瘤浸润淋巴细胞数量减少相关。与之相一致的是，与ATA单倍型患者相比，非ATA单倍型患者外周血中的T细胞更易发生凋亡，且对肿瘤细胞的细胞毒性更弱。本研究结果表明，IL-10可通过促进T细胞凋亡与肿瘤细胞存活加速肿瘤恶性进程；通过PCR-RFLP或直接测序法检测的IL-10单倍型，可用于预测术后NSCLC患者的生存期与复发风险，助力临床医师制定合理的诊疗决策。