de Miguel-Perez Diego, Russo Alessandro, Gunasekaran Muthukumar, Buemi Francesco, Hester Lisa, Fan Xiaoxuan, Carter-Cooper Brandon A, Lapidus Rena G, Peleg Ariel, Arroyo-Hernández Marisol, Cardona Andres F, Naing Aung, Hirsch Fred R, Mack Philip C, Kaushal Sunjay, Serrano Maria Jose, Adamo Vincenzo, Arrieta Oscar, Rolfo Christian
Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, New York, USA.
Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Cancer. 2023 Feb 15;129(4):521-530. doi: 10.1002/cncr.34576. Epub 2022 Dec 9.
Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-β (TGF-β), can be found free in circulation in the blood and packaged into extracellular vesicles (EVs), which have a specific delivery tropism and can affect in tumor/immune system interaction. TGF-β is an immunosuppressive cytokine that plays a crucial role in tumor immune escape, treatment resistance, and metastasis. Thus, we aimed to evaluate the predictive value of circulating and EV TGF-β in patients with non-small-cell lung cancer receiving ICIs.
Plasma samples were collected in 33 patients with advanced non-small-cell lung cancer before and during treatment with ICIs. EV were isolated from plasma by serial ultracentrifugation methods and circulating and EV TGF-β expression levels were evaluated by enzyme-linked immunosorbent assay.
Baseline high expression of TGF-β in EVs was associated with nonresponse to ICIs as well as shorter progression-free survival and overall survival, outperforming circulating TGF-β levels and tissue PD-L1 as a predictive biomarker.
If validated, EV TGF-β could be used to improve patient stratification, increasing the effectiveness of treatment with ICIs and potentially informing combinatory treatments with TGF-β blockade.
Treatment with immune-checkpoint inhibitors (ICIs) has improved the survival of some patients with lung cancer. However, the majority of patients do not benefit from this treatment, making it essential to develop more reliable biomarkers to identify patients most likely to benefit. In this pilot study, the expression of transforming growth factor-β (TGF-β) in blood circulation and in extracellular vesicles was analyzed. The levels of extracellular vesicle TGF-β before treatment were able to determine which patients would benefit from treatment with ICIs and have a longer survival with higher accuracy than circulating TGF-β and tissue PD-L1, which is the currently used biomarker in clinical practice.
免疫检查点抑制剂（ICIs）是一种有效的治疗策略，与传统治疗相比，可提高肺癌患者的生存率。然而，由于目前使用的高度异质性的组织学PD-L1显示出较低的准确性，因此需要新的预测生物标志物来对哪些患者能从临床获益进行分层。液体活检是对体液中的生物标志物进行分析，是一种微创工具，可用于监测肿瘤进展和治疗效果，有可能减少与组织活检相关的肿瘤异质性偏差。在这种情况下，细胞因子，如转化生长因子-β（TGF-β），可以在血液中游离存在，也可以包装到细胞外囊泡（EVs）中，后者具有特定的递送趋向性，并可影响肿瘤/免疫系统相互作用。TGF-β是一种免疫抑制细胞因子，在肿瘤免疫逃逸、治疗耐药和转移中起关键作用。因此，我们旨在评估循环和细胞外囊泡TGF-β在接受ICIs治疗的非小细胞肺癌患者中的预测价值。
收集33例晚期非小细胞肺癌患者在接受ICIs治疗前及治疗期间的血浆样本。通过连续超速离心法从血浆中分离细胞外囊泡，并通过酶联免疫吸附测定法评估循环和细胞外囊泡TGF-β的表达水平。
细胞外囊泡中TGF-β的基线高表达与对ICIs无反应、无进展生存期和总生存期较短相关，作为预测生物标志物，其表现优于循环TGF-β水平和组织PD-L1。
如果得到验证，细胞外囊泡TGF-β可用于改善患者分层，提高ICIs治疗的有效性，并可能为TGF-β阻断联合治疗提供依据。
免疫检查点抑制剂（ICIs）治疗提高了部分肺癌患者的生存率。然而，大多数患者并未从这种治疗中获益，因此开发更可靠的生物标志物以识别最可能获益的患者至关重要。在这项初步研究中，分析了血液循环和细胞外囊泡中转化生长因子-β（TGF-β）的表达。治疗前细胞外囊泡TGF-β水平能够确定哪些患者将从ICIs治疗中获益，并具有更长的生存期，其准确性高于循环TGF-β和组织PD-L1，后者是临床实践中目前使用的生物标志物。
