Differential impact of lipid profile according to neutrophil-to-lymphocyte ratio status in patients with advanced cancer treated with immunotherapy

<b>Aim:</b> To investigate the different impact of each component of lipid profile in advanced cancer patients treated with immune checkpoints inhibitors (ICIs) according to neutrophil-to-lymphocyte ratio (NLR) value. <b>Methods:</b> We retrospectively collected total cholesterol (TC), triglycerides (TGs), low-density lipoproteins (LDL), high-density lipoproteins (HDL). <b>Results:</b> 407 patients were enrolled. In NLR &lt;4 subgroup, TGs &lt;150 mg/dl led to longer PFS (<i>p</i> = 0.01) and OS (<i>p</i> = 0.02) compared with TGs ≥150 mg/dl; LDL &lt;100 mg/dl led to longer PFS (<i>p</i> = 0.004) and OS (<i>p</i> = 0.007) compared with LDL ≥100 mg/dl. In NLR ≥4 subgroup, TC &gt;200 mg/dl led to longer PFS (<i>p</i> = 0.008) and OS (<i>p</i> = 0.004) compared with TC &lt;200 mg/dl. <b>Conclusion:</b> We showed a distinct prognostic impact of lipid profile according to NLR. Preclinical findings suggest a link between lipid metabolism, systemic inflammation and immune cells activity. In this study, the interaction between lipid profile and inflammatory status in cancer patients have been investigated. A total of 407 patients with advanced solid tumors treated with ICIs, alone or in combination with TKIs or chemotherapy, were enrolled in the study. Clinical outcomes were investigated according to lipid profile components, in the whole cohort and in NLR-based subgroups. The negative prognostic value of high NLR have been confirmed in patients with advanced cancer treated with immune checkpoints inhibitors. Components of lipid profile (total cholesterol, triglycerides, HDL, LDL) have a different prognostic impact according to NLR subgroups. High total cholesterol and preserved HDL positively impact on clinical outcomes in patients with NLR ≥4 under immunotherapy treatment. No prognostic impact on clinical outcomes was observed according to total cholesterol and HDL in patients with NLR &lt;4 under immunotherapy treatment. High LDL and high triglycerides negatively impact on clinical outcomes in patients with NLR &lt;4 under immunotherapy treatment. Conversely, no prognostic impact on clinical outcomes was observed according to LDL and triglycerides in patients with NLR ≥4 under immunotherapy treatment. Each component of circulating lipid profile detains distinct prognostic impact according to NLR subgroup. Our results supported the evidence about the close interconnecting between lipid profile and immune-inflammatory system in patients with advanced solid tumors receiving immunotherapy.

**研究目的**：本研究旨在基于中性粒细胞与淋巴细胞比值（neutrophil-to-lymphocyte ratio, NLR）分层，探究血脂谱各组分对接受免疫检查点抑制剂（immune checkpoints inhibitors, ICIs）治疗的晚期癌症患者的差异化预后影响。
**研究方法**：本研究回顾性收集了总胆固醇（total cholesterol, TC）、甘油三酯（triglycerides, TGs）、低密度脂蛋白（low-density lipoproteins, LDL）及高密度脂蛋白（high-density lipoproteins, HDL）相关检测数据。
**研究结果**：本研究共纳入407例患者。在NLR＜4亚组中，TGs＜150 mg/dl的患者相较于TGs≥150 mg/dl者，无进展生存期（progression-free survival, PFS，p=0.01）与总生存期（overall survival, OS，p=0.02）均更长；LDL＜100 mg/dl的患者相较于LDL≥100 mg/dl者，PFS与OS均更长（p=0.004、p=0.007）。在NLR≥4亚组中，TC＞200 mg/dl的患者相较于TC＜200 mg/dl者，PFS与OS均更长（p=0.008、p=0.004）。
**研究结论**：本研究证实，基于NLR分层，血脂谱各组分对患者的预后存在显著差异化影响。临床前研究结果提示，脂代谢、全身炎症与免疫细胞活性之间存在密切关联。本研究即针对癌症患者血脂谱与炎症状态的相互作用展开了探究。本研究共纳入407例接受ICIs单药或联合酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs）或化疗的晚期实体瘤患者。研究对全队列及基于NLR分层的亚组患者，依据血脂谱各组分分析了其临床结局。本研究证实了高NLR对接受ICIs治疗的晚期癌症患者的不良预后价值。血脂谱各组分（总胆固醇、甘油三酯、HDL、LDL）的预后影响随NLR亚组不同而存在差异。在NLR≥4的免疫治疗患者中，高总胆固醇与正常水平HDL可对临床结局产生积极影响。而在NLR＜4的免疫治疗患者中，总胆固醇与HDL水平未对临床结局产生显著预后影响。在NLR＜4的免疫治疗患者中，高LDL与高TGs会对临床结局产生不良影响。反之，在NLR≥4的免疫治疗患者中，LDL与TGs水平未对临床结局产生显著预后影响。循环血脂谱的各组分依据NLR亚组展现出差异化的预后影响。本研究结果进一步证实，接受免疫治疗的晚期实体瘤患者中，血脂谱与免疫炎症系统之间存在紧密的相互关联。