Battaglia Alessandra, Piermattei Alessia, Buzzonetti Alexia, Pasciuto Tina, Zampetti Nicole, Fossati Marco, Angelico Giuseppe, Iacobelli Valentina, Nero Camilla, Iannucci Veronica, Scambia Giovanni, Fagotti Anna, Fattorossi Andrea
Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Department of Women, Children and Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy.
Cancers (Basel). 2021 Oct 16;13(20):5200. doi: 10.3390/cancers13205200.
Ovarian cancer (OC) has recently attracted attention for the use of PD-1/PD-L1 axis blocking agents, with durable activity reported only in a subset of patients. The most used biomarker for sensitivity to the PD-1/PD-L1 axis blockade is tumour PD-L1 status by immunohistochemistry. However, patient stratification using this method suffers from intrinsic heterogeneity of OC, likely contributing to the unsatisfactory results obtained so far. Cells communicate with each other by releasing microvesicles (MVs) that carry parental cell surface features. Thus, we hypothesised that PD-L1 tumour cells (TC) and infiltrating PD-L1 leukocytes should shed MVs carrying surface PD-L1 that may serve as a proxy for the whole tumour PD-L1 status.
We showed for the first time the presence of measurable amounts of TC- and leukocyte-derived PD-L1 MVs (range: 1.4-178.8 MVs/μL and 6.2-504.8 MVs/μL, respectively) in the plasma of high-grade serous OC (HGSOC) patients ( = 63), using a sensitive flow cytometry platform. The concentration of PD-L1 MVs of either origin did not associate with the PD-L1 status of TCs and leukocytes in the tumour biopsies, suggesting that the circulating PD-L1 MVs also included ones from locations not selected for immunohistochemistry analysis and represented the PD-L1 status of the whole tumour mass. In this study, we also describe the serendipitous discovery of circulating PD-L1 MVs of platelet origin (10.3-2409.6 MVs/μL).
The enumeration of circulating PD-L1 MVs in HGSOC patients may provide a novel direction for assessing the tumour PD-L1 status and contribute to HGSOC patient stratification for immunotherapy interventions. The presence of circulating PD-L1 MVs of platelet origin, a finding not yet reported in HGSOC patients, warrants further studies.
卵巢癌（OC）最近因使用PD-1/PD-L1轴阻断剂而受到关注，据报道只有一部分患者有持久疗效。用于评估对PD-1/PD-L1轴阻断敏感性的最常用生物标志物是通过免疫组织化学检测肿瘤PD-L1状态。然而，使用这种方法进行患者分层受到OC内在异质性的影响，这可能是迄今为止结果不尽人意的原因。细胞通过释放携带亲代细胞表面特征的微泡（MVs）相互通讯。因此，我们推测携带表面PD-L1的PD-L1肿瘤细胞（TC）和浸润性PD-L1白细胞释放的MVs可能代表整个肿瘤的PD-L1状态。
我们首次使用灵敏的流式细胞术平台，在63例高级别浆液性OC（HGSOC）患者的血浆中检测到可测量数量的TC来源和白细胞来源的PD-L1 MVs（范围分别为1.4 - 178.8个MVs/μL和6.2 - 504.8个MVs/μL）。两种来源的PD-L1 MVs浓度与肿瘤活检中TC和白细胞的PD-L1状态无关，这表明循环中的PD-L1 MVs还包括来自未选择进行免疫组织化学分析部位的MVs，代表了整个肿瘤块的PD-L1状态。在本研究中，我们还意外发现了血小板来源的循环PD-L1 MVs（10.3 - 2409.6个MVs/μL）。
HGSOC患者循环中PD-L1 MVs的计数可能为评估肿瘤PD-L1状态提供新方向，并有助于HGSOC患者免疫治疗干预的分层。血小板来源的循环PD-L1 MVs的存在（这一发现尚未在HGSOC患者中报道）值得进一步研究。
