Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
BMC Med. 2022 May 13;20(1):187. doi: 10.1186/s12916-022-02356-7.
Cytokines have been reported to alter the response to immune checkpoint inhibitors (ICIs) in patients with the tumor in accordance with their plasma concentrations. Here, we aimed to identify the key cytokines which influenced the responses and stimulated resistance to ICIs and tried to improve immunological response and develop novel clinical treatments in non-small cell lung cancer (NSCLC).
The promising predictive cytokines were analyzed via the multi-analyte flow assay. Next, we explored the correlation baseline level of plasma cytokines and clinical outcomes in 45 NSCLC patients treated with ICIs. The mechanism of the potential candidate cytokine in predicting response and inducing resistance to ICIs was then investigated.
We found NSCLC with a low baseline concentration of IL-6 in plasma specimens or tumor tissues could derive more benefit from ICIs based on the patient cohort. Further analyses revealed that a favorable relationship between PD-L1 and IL-6 expression was seen in NSCLC specimens. Results in vitro showed that PD-L1 expression in the tumor was enhanced by IL-6 via the JAK1/Stat3 pathway, which induced immune evasion. Notably, an adverse correlation was found between IL-6 levels and CD8 T cells. And a positive association between IL-6 levels and myeloid-derived suppressor cells, M2 macrophages and regulator T cells was also seen in tumor samples, which may result in an inferior response to ICIs. Results of murine models of NSCLC suggested that the dual blockade of IL-6 and PD-L1 attenuated tumor growth. Further analyses detected that the inhibitor of IL-6 stimulated the infiltration of CD8 T cells and yielded the inflammatory phenotype.
This study elucidated the role of baseline IL-6 levels in predicting the responses and promoting resistance to immunotherapy in patients with NSCLC. Our results indicated that the treatment targeting IL-6 may be beneficial for ICIs in NSCLC.
据报道,细胞因子会根据其在血浆中的浓度改变肿瘤患者对免疫检查点抑制剂(ICI)的反应。在这里,我们旨在确定影响反应并刺激对 ICI 产生耐药性的关键细胞因子,并试图改善免疫反应并为非小细胞肺癌(NSCLC)开发新的临床治疗方法。
通过多分析物流式细胞术分析有前途的预测细胞因子。接下来,我们探索了 45 名接受 ICI 治疗的 NSCLC 患者的基线血浆细胞因子水平与临床结局之间的相关性。然后研究了潜在候选细胞因子在预测 ICI 反应和诱导耐药性中的作用机制。
我们发现,根据患者队列,基线血浆标本或肿瘤组织中 IL-6 浓度较低的 NSCLC 患者可能从 ICI 中获益更多。进一步分析显示,在 NSCLC 标本中观察到 PD-L1 表达与 IL-6 表达之间存在良好的关系。体外结果表明,IL-6 通过 JAK1/Stat3 通路增强肿瘤中的 PD-L1 表达,从而诱导免疫逃逸。值得注意的是,IL-6 水平与 CD8 T 细胞之间存在负相关。在肿瘤样本中还观察到 IL-6 水平与髓源性抑制细胞、M2 巨噬细胞和调节性 T 细胞之间存在正相关,这可能导致对 ICI 的反应较差。NSCLC 小鼠模型的结果表明,IL-6 和 PD-L1 的双重阻断减弱了肿瘤生长。进一步分析检测到,IL-6 抑制剂刺激了 CD8 T 细胞的浸润,并产生了炎症表型。
本研究阐明了基线 IL-6 水平在预测 NSCLC 患者对免疫治疗的反应和促进耐药性中的作用。我们的结果表明,针对 IL-6 的治疗可能对 NSCLC 的 ICI 有益。