Fraser Christopher C, Jia Bin, Hu Guangan, Al Johani Lojain Ibrahim, Fritz-Klaus Roberta, Ham James Dongjoo, Fichorova Raina N, Elias Kevin M, Cramer Daniel William, Patankar Manish S, Chen Jianzhu
Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Department of Obstetrics and Gynecology, University of Wisconsin-Madison, Madison, Wisconsin.
J Immunol. 2022 May 1;208(9):2227-2238. doi: 10.4049/jimmunol.2001095. Epub 2022 Apr 8.
Malignant ascites is a common clinical problem in ovarian cancer. NK cells are present in the ascites, but their antitumor activity is inhibited. The underlying mechanisms of the inhibition have yet to be fully elucidated. Using an Fcγ receptor-mediated NK cell activation assay, we show that ascites from ovarian cancer patients potently inhibits NK cell activation. Part of the inhibitory activity is mediated by CA125, a mucin 16 fragment shed from ovarian cancer tumors. Moreover, transcriptional analyses by RNA sequencing reveal upregulation of genes involved in multiple metabolic pathways but downregulation of genes involved in cytotoxicity and signaling pathways in NK cells purified from ovarian cancer patient ascites. Transcription of genes involved in cytotoxicity pathways are also downregulated in NK cells from healthy donors after in vitro treatment with ascites or with a CA125-enriched protein fraction. These results show that ascites and CA125 inhibit antitumor activity of NK cells at transcriptional levels by suppressing expression of genes involved in NK cell activation and cytotoxicity. Our findings shed light on the molecular mechanisms by which ascites inhibits the activity of NK cells and suggest possible approaches to reactivate NK cells for ovarian cancer immunotherapy.
恶性腹水是卵巢癌常见的临床问题。自然杀伤（NK）细胞存在于腹水中，但其抗肿瘤活性受到抑制。这种抑制的潜在机制尚未完全阐明。通过一种Fcγ受体介导的NK细胞激活试验，我们发现卵巢癌患者的腹水能有效抑制NK细胞的激活。部分抑制活性由CA125介导，CA125是从卵巢癌肿瘤脱落的粘蛋白16片段。此外，通过RNA测序进行的转录分析显示，从卵巢癌患者腹水中纯化出的NK细胞中，参与多种代谢途径的基因上调，但参与细胞毒性和信号通路的基因下调。在用腹水或富含CA125的蛋白组分进行体外处理后，健康供体的NK细胞中参与细胞毒性途径的基因转录也下调。这些结果表明，腹水和CA125通过抑制参与NK细胞激活和细胞毒性的基因表达，在转录水平上抑制NK细胞的抗肿瘤活性。我们的研究结果揭示了腹水抑制NK细胞活性的分子机制，并为卵巢癌免疫治疗中重新激活NK细胞提供了可能的方法。
