Background:The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal carcinoma (NPC), and the specific biomarker determining the response to immunotherapy in NPC remains uncertain.

Methods:We assessed the associations between pre-immunotherapy and post-immunotherapy serum lipoproteins and survival in a training cohort (N=160) and corroborated these findings in a validation cohort (N=100). Animal studies were performed to explore the underlying mechanisms. Additionally, the relationship between high-density lipoprotein-cholesterol (HDL-C) levels and M1/M2-like macrophages, as well as activated CD8+T cells in tumor tissues from patients with NPC who received immunotherapy, was investigated.

Results:The lipoproteins cholesterol, HDL-C, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein A-1 (ApoA1), and apolipoprotein B, were significantly altered after immunotherapy. Patients with higher baseline HDL-C or ApoA1, or those with increased HDL-C or ApoA1 after immunotherapy had longer progression-free survival, a finding verified in the validation cohort (p<0.05). Multivariate analysis revealed that baseline HDL-C and elevated HDL-C post-immunotherapy were independent predictors of superior PFS (p<0.05). Furthermore, we discovered that L-4F, an ApoA1 mimetic, could inhibit tumor growth in NPC xenografts. This effect was associated with L-4F's ability to polarize M2-like macrophages towards an M1-like phenotype via the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65, thereby alleviating immunosuppression in the tumor microenvironment. Importantly, in patients with NPC with high plasma HDL-C levels, the number of M2-like macrophages was significantly decreased, while M1-like macrophages and activated CD8+T cells were notably increased in those with high HDL-C levels.

Conclusion:Higher baseline HDL-C levels or an increase in HDL-C post-immunotherapy can enhance immunotherapeutic responses in patients with NPC by reprogramming M2-like macrophages towards the M1 phenotype. This suggests a potential role for prospectively exploring ApoA1 mimetics as adjuvant agents in combination with immunotherapy.

本周为大家带来的文献为发表于J Immunother Cancer. (IF: 10.3)的” HDL-cholesterol confers sensitivity of immunotherapy in nasopharyngeal carcinoma via remodeling tumor-associated macrophages towards the M1 phenotype”。本文使用了LabEx提供的Luminex检测服务。

 

尽管免疫检查点抑制剂（ICIs）为包括鼻咽癌（NPC）在内的多种实体瘤开创了一个全新的治疗时代，但只有约 20% 的鼻咽癌患者能从单药免疫疗法中获益，而且抗肿瘤反应并不持久。尽管如此，人们仍在寻找能够预测ICIs 对鼻咽癌疗效的可靠生物标志物。鼻咽癌患者原有的高密度脂蛋白胆固醇（HDL-C）水平较高，或接受免疫治疗后 HDL-C 水平升高，都会使M2样巨噬细胞重置为M1表型，从而增强免疫治疗反应。

 

 

LabEx提供的Luminex检测服务：

为了确定L-4F即使在免疫成分存在的情况下也能调节促炎和抗炎细胞因子的产生，研究者还从接受L-4F或SC-4F处理的免疫功能正常的C57BL/6小鼠体内收集了PBMCs，并对细胞因子进行了检测。细胞因子检测结果显示，L-4F 处理后，M1 相关细胞因子显著升高，M2 相关细胞因子明显降低，这与 SCID 小鼠中观察到的结果一致。

 

  

 

L-4F 通过激活 p38 和 NF-κB 通路诱导 M1 样巨噬细胞极化。(A) 经 L-4F 或 SC-4F 处理的小鼠 BMDMs 暴露于 LLC 细胞 CM 和 C57BL/6 小鼠 PBMCs 24 小时后的 Bio-Plex Pro 小鼠趋化因子检测结果。

 

 

重要发现：

免疫疗法后，脂蛋白胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、甘油三酯、载脂蛋白A-1（载脂蛋白A1）和载脂蛋白B都发生了显著变化。基线高密度脂蛋白胆固醇或载脂蛋白A1较高或免疫治疗后高密度脂蛋白胆固醇或载脂蛋白A1升高的患者无进展生存期较长，这一结果在验证队列中得到了验证（P<0.05）。多变量分析显示，基线高密度脂蛋白胆固醇和免疫治疗后高密度脂蛋白胆固醇升高是预测较好无进展生存期的独立因素（P<0.05）。此外，我们还发现载脂蛋白A1模拟物L-4F能抑制鼻咽癌异种移植的肿瘤生长。这种效应与 L-4F 能够通过激活丝裂原活化蛋白激酶 (MAPK) p38 和核因子-κB (NF-κB) p65 将 M2 样巨噬细胞极化为 M1 样表型，从而减轻肿瘤微环境中的免疫抑制有关。重要的是，在血浆高密度脂蛋白胆固醇水平较高的鼻咽癌患者中，M2样巨噬细胞的数量明显减少，而在高密度脂蛋白胆固醇水平较高的患者中，M1样巨噬细胞和活化的CD8+T细胞明显增加。