HDL-cholesterol confers sensitivity of immunotherapy in nasopharyngeal carcinoma via remodeling tumor-associated macrophages towards the M1 phenotype

作者：Fan Luo, Jiaxin Cao, Qun Chen, Lusha Liu, Ting Yang, Xue Bai, Wenjuan Ma, Chaozhuo Lin, Ting Zhou, Jianhua Zhan, Yan Huang, Yunpeng Yang, Hongyun Zhao, Li Zhang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2024 · DOI：10.1136/jitc-2023-008146 · 被引用次数：16 · 研究领域：Cancer, Lipids, and Metabolism、Immune cells in cancer、Inflammatory Biomarkers in Disease Prognosis

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 ...