PO.IM02.05 · 免疫学
多组学分析提名SPP1-IL10轴为胃腹膜癌病的新型免疫治疗靶点
Multi-omic analysis nominates SPP1-IL10 axis as a novel immunotherapeutic target in gastric peritoneal carcinomatosis
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摘要 Abstract
中文摘要
胃癌是全球癌症相关死亡的第三大原因。腹膜是最常见的转移部位，占复发的60%。腹膜癌病导致65%的胃癌相关死亡，中位总生存期为6-9个月。因此，鉴定新型疗法仍是一项未满足的临床需求。SPP1（osteopontin，骨桥蛋白）是一种参与多种生物学功能的糖蛋白，由良性和恶性细胞分泌。其在胃癌病中的作用尚不明确。利用公开可得的转录组数据集，我们表明SPP1在胃腹膜转移和恶性腹水中过表达。批量分析和单细胞分析表明，SPP1表达与肿瘤微环境中巨噬细胞浸润呈正相关。SPP1突变型肿瘤富集巨噬细胞排斥表型。与人类数据相符，细胞因子阵列分析鉴定出小鼠胃肿瘤细胞SPP1分泌升高。重组SPP1促进巨噬细胞迁移并在体外抑制IL-10的分泌。来自人恶性腹水单细胞测序数据集的细胞间信号网络揭示SPP1+上皮细胞调控巨噬细胞的IL-10表达。使用胃腹膜癌病的同基因小鼠模型，我们观察到靶向SPP1阻断减少了肿瘤生长，表现为肿瘤重量和腹膜结节数量减少50%。此外，SPP1阻断抑制了体内巨噬细胞的迁移和IL-10的分泌。总之，我们揭示了一种癌细胞-巨噬细胞串扰的新机制，提示靶向SPP1可能有效地重编程胃腹膜癌病中的肿瘤微环境。
查看英文原文 English abstract
Gastric cancer is 3 rd leading cause of cancer-related mortality worldwide. The peritoneum is the most common site of metastasis, accounting for 60% of recurrences. Peritoneal carcinomatosis results in 65% of gastric cancer-associated deaths, resulting in a median overall survival of 6-9 months. Therefore, identifying novel therapies remains a clinically unmet need. SPP1 (osteopontin) is a glycoprotein involved in diverse biological functions. It is secreted by benign and malignant cells. Its role in gastric carcinomatosis is not well defined. Utilizing publicly available transcriptomic datasets, we show that SPP1 is overexpressed in gastric peritoneal metastasis and malignant ascites. Bulk and single-cell analysis demonstrated that SPP1 expression positively correlated with macrophage infiltration in the tumor microenvironment. SPP1 mutant tumors were enriched for macrophage-excluded phenotype. In conjunction with the human data, cytokine array analysis identified elevated SPP1 secretion by murine gastric tumor cells. Recombinant SPP1 promoted macrophage migration and inhibited the secretion of IL-10 in-vitro. Intercellular signaling networks from single-cell sequencing data sets of human malignant ascites revealed SPP1+ epithelial cells regulate macrophage expression of IL-10. Using syngeneic murine models of gastric peritoneal carcinomatosis, we observed that targeted SPP1 blockade diminished tumor growth as demonstrated by a 50% decrease in tumor weight and number of peritoneal nodules. In addition, in-vivo macrophage trafficking and secretion of IL-10 were inhibited by SPP1 blockade. In summary, we have uncovered a novel mechanism of cancer-macrophage crosstalk, suggesting that targeting SPP1 may be effective for reprogramming of the tumor microenvironment in gastric peritoneal carcinomatosis
利益披露 Disclosure
T. Lilia, None..
N. Hosamani, None..
E. Beswick, None..
J. Kim, None..
M. Barry-Hundeyin, None.