肿瘤细胞治疗研究
英文原题：Invariant Natural Killer T Cell Therapy Attenuates Systemic Inflammation and Improves Transarterial Chemoembolization Outcomes in Hepatocellular Carcinoma.
背景：恒定自然杀伤T（iNKT）细胞作为实体瘤免疫治疗剂展现出前景，我们先前的研究表明，将iNKT细胞疗法与经动脉化疗栓塞（TACE）联合治疗肝细胞癌（HCC）获得了58.3%的客观缓解率（ORR）。
背景：恒定自然杀伤T（iNKT）细胞作为实体瘤免疫治疗药物展现出前景，我们先前的研究表明，将iNKT细胞治疗与经动脉化疗栓塞（TACE）联合使用在肝细胞癌（HCC）中达到了58.3%的客观缓解率（ORR）。本研究进一步探讨iNKT介导的免疫调节对TACE后生存动态及相关预后生物标志物的影响。方法：获取2018-2023年间北京佑安医院77例HCC患者的临床数据和外周血样本，其中38例仅接受TACE治疗，39例接受iNKT细胞/TACE联合治疗。连续测量包括：血液学参数；肝功能检查[丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、胆红素]；炎症标志物[C反应蛋白（CRP）、中性粒细胞与淋巴细胞比值（NLR）]；细胞因子谱[干扰素-γ（IFN-γ）、白细胞介素-6（IL-6）、白细胞介素-10（IL-10）]。通过单因素/多因素Cox回归确定无进展生存期（PFS）的潜在预后因素。使用多因素分析中的显著协变量推导风险评分模型。通过时间依赖性受试者工作特征（ROC）分析[曲线下面积（AUC）计算]和Kaplan-Meier生存分层及log-rank检验评估模型性能。结果：TACE组治疗后淋巴细胞减少但中性粒细胞/单核细胞增加，而iNKT + TACE组维持稳定计数。全身炎症指标[NLR/全身免疫炎症指数（SII）/全身炎症反应指数（SIRI）]在单纯TACE组显著升高（均p < 0.05），但在iNKT + TACE组保持稳定。细胞因子谱分析显示，与TACE相比，iNKT + TACE组IL-6/IL-10降低（p < 0.001/ p = 0.012），IFN-γ/肿瘤坏死因子-alpha（TNF-α）升高（p < 0.01/ p < 0.001）。多因素分析确定淋巴细胞计数（HR = 0.18，95%CI 0.04-0.76，p = 0.02）、IL-6（HR = 2.57，95%CI 1.03-6.86，p = 0.04）和IFN-γ（HR = 0.14，95%CI 0.02-0.98，p = 0.04）为独立的PFS预测因子。风险模型显示出较强的区分能力（AUC = 0.891，95%CI 0.73-1.00），在iNKT + TACE组中，低风险组与高风险组的中位PFS分别为9.5个月与3.0个月（log-rank p < 0.01）。结论：iNKT细胞治疗可稳定HCC患者外周血淋巴细胞计数并减轻TACE诱导的炎症。淋巴细胞水平、IL-6和IFN-γ的联合评估是iNKT + TACE治疗患者PFS的一个有前景的预后生物标志物组合。
Background: Invariant natural killer T (iNKT) cells show promise as immunotherapeutic agents for solid tumors, and our prior study demonstrated that combining iNKT-cell therapy with transarterial chemoembolization (TACE) achieved a 58.3% objective response rate (ORR) in hepatocellular carcinoma (HCC). This study further examines iNKT-mediated immune modulation of post-TACE survival dynamics and associated prognostic biomarkers. Methods: Clinical data and peripheral blood samples were obtained from 77 HCC patients in Beijing you'an Hospital between 2018-2023, including 38 receiving TACE alone and 39 receiving combined iNKT-cell/TACE therapy. Serial measurements included: Hematological parameters; Liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin]; Inflammatory markers [C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR)]; Cytokine profiling [Interferon-gamma (IFN-γ), Interleukin-6 (IL-6), Interleukin-10 (IL-10)]. Potential Prognostic factors for progression-free survival (PFS) were identified through univariate/multivariate Cox regression. A risk-score model was derived using significant covariates from the multivariate analysis. Model performance was evaluated by time-dependent receiver operating characteristic (ROC) analysis [Area Under the Curve (AUC) calculation] and Kaplan-Meier survival stratification with log-rank testing. Results: The TACE group exhibited decreased lymphocytes but increased neutrophils/monocytes post-treatment, whereas iNKT + TACE maintained stable counts. Systemic inflammation indices [NLR/systemic immune-inflammation Index (SII)/systemic inflammation response index (SIRI)] rose significantly in TACE alone (all p < 0.05) but remained stable in iNKT + TACE. Cytokine profiling revealed reduced IL-6/IL-10 ( p < 0.001/ p = 0.012) and elevated IFN-γ/tumor necrosis factor-alpha (TNF-α) ( p < 0.01/ p < 0.001) in iNKT + TACE vs. TACE. Multivariate analysis identified lymphocyte count (HR = 0.18, 95%CI 0.04-0.76, p = 0.02), IL-6 (HR = 2.57, 95%CI 1.03-6.86, p = 0.04), and IFN-γ (HR = 0.14, 95%CI 0.02-0.98, p = 0.04) as independent PFS predictors. The risk model demonstrated strong discrimination (AUC = 0.891, 95%CI 0.73-1.00), with median PFS of 9.5 vs. 3.0 months for low- vs. high-risk groups (log-rank p < 0.01) in iNKT + TACE group. Conclusions: iNKT cell therapy stabilizes peripheral lymphocyte counts and attenuates TACE-induced inflammation in HCC. The combined evaluation of lymphocyte levels, IL-6, and IFN-γ represents a promising prognostic biomarker panel for PFS in iNKT + TACE-treated patients.
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