Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
Food and Drug Department, University of Parma, Parma, Italy.
Cancer Immunol Immunother. 2023 Jul;72(7):2127-2135. doi: 10.1007/s00262-023-03398-3. Epub 2023 Feb 24.
Immune checkpoint inhibitors (ICIs) became the standard of care for several solid tumors. A limited fraction of patients (pts) achieves a long-term benefit. Plasmatic and intracellular cholesterol levels have emerged as promising biomarkers. The aim of the present study was to determine whether cholesterol efflux capacity (CEC), mediated by serum transporters (ABCA1 and ABCG1) and passive diffusion (PD), impacts on clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs.
We retrospectively enrolled advanced NSCLC and mRCC pts consecutively treated with ICIs between October 2013 and October 2018. CEC and cholesterol loading capacity (CLC) were assessed by well-established specific cell models. As primary endpoint, CEC, PD and CLC were correlated with overall survival (OS) while the effects of these parameters on progression-free survival (PFS) and clinical benefit (CB), defined as complete/partial response or stable disease, represented secondary endpoints.
NSCLC accounted for 94.2% of 70 enrolled cases, and serum sample suitable for CEC and PD determination was available in 68. Blood cholesterol and serum ABCA1, ABCG1, PD and CLC were associated with outcomes (OS, PFS and CB) at univariate analysis. At the multivariate analysis, only PD confirmed its positive prognostic value in terms of OS, PFS and CB.
The favorable impact of cholesterol PD on clinical outcome might reflect its main conformation in mature HDL particles which potentially shape an inflamed context, ultimately promoting ICI efficacy. Further prospective studies are needed to support our findings and uncover targetable pathways.
免疫检查点抑制剂（ICIs）已成为多种实体瘤的标准治疗方法。只有有限比例的患者（pts）能获得长期获益。血浆和细胞内胆固醇水平已成为有前途的生物标志物。本研究旨在确定胆固醇外排能力（CEC），由血清转运蛋白（ABCA1 和 ABCG1）和被动扩散（PD）介导，是否会影响接受 ICI 治疗的晚期非小细胞肺癌（NSCLC）和转移性肾细胞癌（mRCC）患者的临床结局。
我们回顾性纳入了 2013 年 10 月至 2018 年 10 月期间连续接受 ICI 治疗的晚期 NSCLC 和 mRCC 患者。通过成熟的特定细胞模型评估 CEC 和胆固醇负载能力（CLC）。作为主要终点，CEC、PD 和 CLC 与总生存期（OS）相关，而这些参数对无进展生存期（PFS）和临床获益（CB）的影响（定义为完全/部分缓解或疾病稳定）作为次要终点。
70 例入组患者中 NSCLC 占 94.2%，68 例患者有适合 CEC 和 PD 测定的血清样本。血胆固醇和血清 ABCA1、ABCG1、PD 和 CLC 在单因素分析中与结局（OS、PFS 和 CB）相关。在多因素分析中，只有 PD 证实其在 OS、PFS 和 CB 方面具有良好的预后价值。
胆固醇 PD 对临床结局的有利影响可能反映了其在成熟 HDL 颗粒中的主要构象，这可能形成一个炎症环境，最终促进 ICI 的疗效。需要进一步的前瞻性研究来支持我们的发现并揭示可靶向的途径。
