Dynamic Change of PD‐L2 on Circulating Plasma Extracellular Vesicles as a Predictor of Treatment Response in Melanoma Patients Receiving Anti‐PD‐1 Therapy

黑色素瘤 颗粒酶B 免疫系统 CD8型 医学 外周血单个核细胞 免疫学 癌症研究 体内 不利影响 微泡 肿瘤科 内科学 体外 生物 小RNA 生物技术 基因 生物化学
作者
Linzi Sun,Xiaoting Wei,Qian Zhao,Lili Mao,Xue Bai,Caili Li,Junjie Gu,Yan Kong,Chuanliang Cui,Zhihong Chi,Xinan Sheng,Bin Lian,Xuan Wang,Siming Li,Xieqiao Yan,Bixia Tang,Li Zhou,Juan Li,Jun Guo,Lu Si
出处
期刊:Journal of extracellular vesicles [Taylor & Francis]
卷期号:14 (4)
标识
DOI:10.1002/jev2.70054
摘要

Immune checkpoint inhibitors (ICIs) have provided new hope for melanoma patients, however, not all patients benefit. Furthermore, ICI-related therapies cause significant immune-related adverse events that adversely affect patient outcomes. Therefore, there is a pressing need for reliable biomarkers to identify patients most likely to benefit from these treatments. In this study, we employed an extracellular vesicles (EVs) protein expression array to explore the longitudinal membrane protein profiles of plasma-derived EVs from 32 melanoma patients receiving anti-PD-1 and anti-angiogenesis therapy at baseline and early treatment. We found that the dynamic changes in PD-L2 on the EV membrane were associated with treatment response and patient survival. The dynamic change of EV PD-L2 as an indication of treatment efficacy was validated in an independent cohort of melanoma patients treated with anti-PD-1 monotherapy. Plasma-derived PD-L2+ EVs from patients with mucosal melanoma significantly reduced the frequency of granzyme B+ CD8 T cells within the peripheral blood mononuclear cells (PBMCs) of healthy individuals. The inhibitory effect of PD-L2+ EVs on CD8 T cells was further validated using human melanoma cell lines and the B16-F10 mouse model. Although intratumoural injection of PD-L2+ EVs could promote melanoma growth in vivo, tumours with PD-L2+ EVs showed a higher response to anti-PD-1 than those without PD-L2+ EVs. Collectively, our study demonstrates that PD-L2+ EVs inhibit CD8 T cell activation and promote melanoma growth, and changes in PD-L2 on circulating EVs during early treatment could serve as a biomarker for ICI-based therapy.

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