Baxter Laboratory for Stem Cell Biology, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Urology Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Rep. 2021 Aug 31;36(9):109632. doi: 10.1016/j.celrep.2021.109632.
Tubo-ovarian high-grade serous carcinoma (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we apply mass cytometry and uncover decidual-like natural killer (dl-NK) cell subpopulations (CD56+CD9+CXCR3+KIR+CD3-CD16-) in newly diagnosed HGSC samples that correlate with both tumor and transitioning epithelial-mesenchymal cell abundance. We show different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within three HGSC tumor compartments: epithelial (E), transitioning epithelial-mesenchymal (EV), and mesenchymal (vimentin expressing [V]), with a more inhibitory ligand phenotype in V cells. In cocultures, NK-92 natural killer cells acquire CD9 from HGSC tumor cells by trogocytosis, resulting in reduced anti-tumor cytokine production and cytotoxicity. Cytotoxicity in these cocultures is restored with a CD9-blocking antibody or CD9 CRISPR knockout, thereby identifying mechanisms of immune suppression in HGSC. CD9 is widely expressed in HGSC tumors and so represents an important new therapeutic target with immediate relevance for NK immunotherapy.
尽管 T 细胞耗竭的频率很高，但卵巢高级别浆液性癌（HGSC）对免疫检查点阻断无反应。在这里，我们应用质谱细胞术并在新诊断的 HGSC 样本中发现蜕膜样自然杀伤（dl-NK）细胞亚群（CD56+CD9+CXCR3+KIR+CD3-CD16-），其与肿瘤和过渡上皮-间充质细胞丰度相关。我们在三个 HGSC 肿瘤区室（上皮[E]、过渡上皮-间充质[EV]和间充质[表达波形蛋白[vimentin]的[v]）中显示出 NK 受体的激活和抑制性配体的不同组合表达模式，V 细胞中具有更抑制性的配体表型。在共培养物中，NK-92 自然杀伤细胞通过胞饮作用从 HGSC 肿瘤细胞中获得 CD9，导致抗肿瘤细胞因子产生和细胞毒性降低。用 CD9 阻断抗体或 CD9 CRISPR 敲除可恢复这些共培养物中的细胞毒性，从而确定了 HGSC 中免疫抑制的机制。CD9 在 HGSC 肿瘤中广泛表达，因此代表了一个重要的新治疗靶点，对 NK 免疫治疗具有直接意义。
