肿瘤细胞治疗研究
英文原题：IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function.
16.63 个月，P = 0.001）和 OS（中位：15.63 vs.
晚期非小细胞肺癌（NSCLC）一线化学免疫治疗的原发性耐药仍是重大挑战。尽管白细胞介素-6（IL-6）等细胞因子被认为与免疫检查点抑制剂（ICI）单药耐药有关，但其对化学免疫治疗结局的预测价值及其潜在机制尚未明确。本研究考察基线血浆IL-6水平的预后意义及该细胞因子塑造NSCLC肿瘤免疫微环境（TIME）的作用。我们回顾性分析了123例接受抗PD-1抑制剂联合化疗的晚期NSCLC患者数据，使用ELISA检测基线血浆IL-6水平，并通过Kaplan-Meier法和Cox回归评估无进展生存（PFS）和总生存（OS）。我们建立IL-6过表达或抑制的小鼠肺腺癌（LLC）和鳞状细胞癌（KLN205）模型，并给予抗PD-1治疗联合化疗。研究监测肿瘤生长，并对肿瘤浸润免疫细胞进行单细胞RNA测序（scRNA-seq）。结果显示，基线血浆IL-6较高（>7.002 pg/mL）的患者较IL-6较低者PFS显著更差（中位数7.20比16.63个月，P=0.001），OS也更差（中位数15.63比32.80个月，P=0.001）。IL-6高水平是PFS较差（HR=2.42，P<0.001）和OS较差（HR=2.96，P<0.001）的独立预测因子，并与疾病进展（PD）相关（P=0.018）。在小鼠模型中，IL-6过表达削弱了抗PD-1联合化疗的抗肿瘤疗效。scRNA-seq分析还显示，IL-6过表达使巨噬细胞极化偏向免疫抑制表型（特征为Hilpda和Nr4a1表达），降低细胞毒性CD8⁺ T细胞比例并增加调节性T细胞（Treg）比例。相反，抑制IL-6促进免疫刺激型巨噬细胞表型（Ccl8表达升高），并增强CD8⁺ T细胞浸润和功能。IL-6高水平还与NK细胞脱颗粒通路受损相关。这些发现表明，基线血浆IL-6升高是晚期NSCLC患者接受化学免疫治疗时原发性耐药和生存较差的可靠独立预测因子。机制上，IL-6通过促进促肿瘤巨噬细胞极化驱动免疫抑制性TIME形成，继而抑制细胞毒性T细胞浸润、促进Treg扩增并损害NK细胞功能，提示靶向IL-6可能是克服化学免疫治疗耐药的有前景策略。
Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, we retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression or inhibition and treated them with anti-PD-1 therapy chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P = 0.001) and OS (median: 15.63 vs. 32.80 months, P = 0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR = 2.42, P < 0.001) and OS (HR = 2.96, P < 0.001) and was correlated with progressive disease (PD, P = 0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8 + T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8 + T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.
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