Department of Histopathology, Trinity College Dublin, Dublin, Ireland.
Emer Casey Research Laboratory, Coombe Women and Infants University Hospital, Dublin, Ireland.
PLoS One. 2019 Mar 25;14(3):e0211538. doi: 10.1371/journal.pone.0211538. eCollection 2019.
Tumour cell immune evasion is a principal hallmark of successful metastasis. Tumour cells in the vasculature adopt a platelet cloak that efficiently suppresses the innate immune system by directly inhibiting Natural Killer (NK) cells, which normally function to neutralise spreading cancers. Here we describe two novel mechanisms of tumour cell evasion of NK cell anti-tumour functions. The first, an 'immune decoy' mechanism in which platelets induce the release of soluble NKG2D ligands from the tumour cell to mask detection and actively suppress NK cell degranulation and inflammatory cytokine (IFNγ) production, concomitantly. This represents a double-hit to immune clearance of malignant cells during metastasis. The second mechanism, a platelet-derived TGFβ-mediated suppression of the CD226/CD96-CD112/CD155 axis, is a novel pathway with poorly understood anti-cancer functions. We have demonstrated that platelets robustly suppress surface expression of CD226 and CD96 on the NK cell surface and their associated ligands on the tumour cell to further enhance NK cell suppression. These highly evolved mechanisms promote successful tumour immune evasion during metastasis and provide a unique opportunity for studying the complexity of cellular interactions in the metastatic cascade and thus novel targets for cancer immunotherapy.
肿瘤细胞的免疫逃逸是转移成功的主要标志。血管中的肿瘤细胞采用血小板“伪装”，通过直接抑制自然杀伤 (NK) 细胞来有效抑制固有免疫系统，而 NK 细胞通常的功能是中和扩散的癌症。在这里，我们描述了肿瘤细胞逃避 NK 细胞抗肿瘤功能的两种新机制。第一种是“免疫诱饵”机制，其中血小板诱导肿瘤细胞释放可溶性 NKG2D 配体，以掩盖检测并主动抑制 NK 细胞脱颗粒和炎症细胞因子（IFNγ）的产生，同时进行。这代表了转移过程中恶性细胞免疫清除的双重打击。第二种机制是血小板衍生的 TGFβ 介导的抑制 CD226/CD96-CD112/CD155 轴，这是一种具有鲜为人知的抗癌功能的新途径。我们已经证明，血小板强烈抑制 NK 细胞表面的 CD226 和 CD96 及其相关配体的表达，从而进一步增强 NK 细胞的抑制作用。这些高度进化的机制促进了转移过程中肿瘤的免疫逃逸，并为研究转移级联中细胞相互作用的复杂性提供了独特的机会，从而为癌症免疫治疗提供了新的靶点。
