循环细胞外囊泡表达 PD1 和 PD-L1 可预测转移性黑色素瘤对检查点抑制剂免疫治疗的反应并介导耐药性。
Circulating extracellular vesicles expressing PD1 and PD-L1 predict response and mediate resistance to checkpoint inhibitors immunotherapy in metastatic melanoma.
机构信息
Laboratory of Nanotechnology, IRCCS Istituto Tumori Giovanni Paolo II, V.le O. Flacco, 65, 70124, Bari, Italy.
Rare Tumors and Melanoma Unit, IRCCS Istituto Tumori Giovanni Paolo II, V.le O. Flacco, 65, 70124, Bari, Italy.
出版信息
Mol Cancer. 2022 Jan 18;21(1):20. doi: 10.1186/s12943-021-01490-9.
BACKGROUND
The immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1 EV mediate resistance to anti-PD1, instead the role of PD1 EV is not fully understood.
METHODS
We isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1 EVs and PD1EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1 EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.
RESULTS
The level of PD-L1 EVs released from melanoma and CD8T cells and that of PD1 EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1 EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1 EVs, from T cells and B cells, and high level of PD-L1 EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1 EVs from melanoma and PD1 EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.
CONCLUSION
Our study identified circulating PD1 EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.
背景
免疫检查点抑制剂（ICI）的免疫疗法改变了转移性黑色素瘤（MM）患者的预期寿命。然而，仍有部分患者对此无应答，因此，确定和验证ICI 反应的新型生物标志物至关重要。循环细胞外囊泡（EVs），如 PD-L1 EV，介导对抗 PD1 的耐药性，而 PD1 EV 的作用尚未完全阐明。
方法
我们从 71 例转移性黑色素瘤患者的观察性队列研究的血浆中分离出循环 EVs，并将 PD-L1 EVs 和 PD1EVs 的数量与 ICI 的反应相关联。根据 EVs 来源于肿瘤和免疫细胞的不同，对分析结果进行了分类。随后，我们在 22 例 MM 患者的验证队列中分析了数据，以评估所确定的基于 EV 的生物标志物的可靠性。此外，我们还评估了 PD1 EVs 对纳武单抗的抑制作用以及对免疫细胞介导的黑色素瘤球体杀伤作用的干扰。
结果
非应答者释放的黑色素瘤和 CD8T 细胞来源的 PD-L1 EVs 水平以及无论细胞来源如何的 PD1 EVs 水平均较高。Kaplan-Meier 曲线表明，较高水平的 PD1+EVs 与较差的无进展生存期（PFS）和总生存期（OS）显著相关。仅当黑色素瘤和 T 细胞释放 PD-L1 EVs 时，才发现显著相关性。多变量分析显示，高水平的 PD1 EVs，来自 T 细胞和 B 细胞，以及高水平的 PD-L1 EVs，来自黑色素瘤细胞，是反应的独立生物标志物。通过单变量 Cox 风险回归分析，在验证队列中，通过单变量 Cox 风险回归分析，验证了黑色素瘤 PD-L1 EVs 和 T 细胞 PD1 EVs 预测 PFS 的可靠性。此外，我们发现，循环 EVs 捕获了纳武单抗，并减少了 T 细胞的迁移和肿瘤球体的杀伤。
结论
我们的研究确定了循环 PD1 EVs 是抗 PD1 耐药的驱动因素，并强调了通过液体活检分析单个 EV 群体是对 MM 患者进行免疫治疗分层的有前途的工具。
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