Immunotherapy has revolutionized the treatment of patients with non-small cell lung cancer (NSCLC). High expression of tissue PD-L1 (tPD-L1) is currently the only approved biomarker for predicting treatment response. However, even tPD-L1 low (1-49%) and absent (<1%) patients might benefit from immunotherapy but, to date, there is no reliable biomarker, that can predict response in this particular patient subgroup. This study aimed to test whether tumour-associated extracellular vesicles (EVs) could fill this gap. Using NSCLC cell lines, we identified a panel of tumour-related antigens that were enriched on large EVs (lEVs) compared to smaller EVs. The levels of lEVs carrying these antigens were significantly elevated in plasma of NSCLC patients (n = 108) and discriminated them from controls (n = 77). Among the tested antigens, we focused on programmed cell death ligand 1 (PD-L1), which is a well-known direct target for immunotherapy. In plasma lEVs, PD-L1 was mainly found on a population of CD45⁻/CD62P⁺ lEVs and thus seemed to be associated with platelet-derived vesicles. Patients with high baseline levels of PD-L1⁺ lEVs in blood showed a significantly better response to immunotherapy and prolonged survival. This was particularly true in the subgroup of NSCLC patients with low or absent tPD-L1 expression, thus identifying PD-L1-positive lEVs in plasma as a novel predictive and prognostic marker for immunotherapy.

中文翻译：

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大细胞外囊泡上的 PD-L1 是组织 PD-L1 低和阴性非小细胞肺癌患者治疗反应的预测生物标志物

免疫疗法彻底改变了非小细胞肺癌（NSCLC）患者的治疗方法。高表达的组织 PD-L1 (tPD-L1) 是目前唯一被批准用于预测治疗反应的生物标志物。然而，即使 tPD-L1 低（1-49%）和缺失（<1%）的患者也可能从免疫治疗中受益，但迄今为止，还没有可靠的生物标志物可以预测这一特定患者亚组的反应。本研究旨在测试肿瘤相关细胞外囊泡（EV）是否可以填补这一空白。使用 NSCLC 细胞系，我们鉴定了一组肿瘤相关抗原，与较小的 EV 相比，这些抗原在大 EV (lEV) 上富集。携带这些抗原的 IEV 水平在 NSCLC 患者 ( n  = 108) 血浆中显着升高，并将其与对照组 ( n  = 77) 区分开来。在测试的抗原中，我们重点关注程序性细胞死亡配体 1 (PD-L1)，它是众所周知的免疫疗法的直接靶点。^{在血浆 IEV 中，PD-L1 主要发现于 CD45 -} /CD62P ⁺ IEV群体中，因此似乎与血小板衍生的囊泡有关。^{血液中 PD-L1 +} lEV基线水平较高的患者对免疫治疗的反应明显更好，生存期也更长。在 tPD-L1 表达低或缺失的 NSCLC 患者亚组中尤其如此，因此将血浆中的 PD-L1 阳性 lEV 确定为免疫治疗的新型预测和预后标志物。