Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is one of the causes of tumor immune tolerance and failure of cancer immunotherapy. Here, we found that bladder cancer (BCa)-derived exosomal circRNA_0013936 could enhance the immunosuppressive activity of PMN-MDSCs by regulating the expression of fatty acid transporter protein 2 (FATP2) and receptor-interacting protein kinase 3 (RIPK3). However, the underlying mechanism remains largely unknown. BCa-derived exosomes was isolated and used for a series of experiments. RNA sequencing was used to identify the differentially expressed circRNAs. Western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, ELISA and Flow cytometry were performed to reveal the potential mechanism of circRNA_0013936 promoting the immunosuppressive activity of PMN-MDSC. CircRNA_0013936 enriched in BCa-derived exosomes could promote the expression of FATP2 and inhibit the expression of RIPK3 in PMN-MDSCs. Mechanistically, circRNA_0013936 promoted the expression of FATP2 and inhibited the expression of RIPK3 expression via sponging miR-320a and miR-301b, which directly targeted JAK2 and CREB1 respectively. Ultimately, circRNA_0013936 significantly inhibited the functions of CD8+ T cells by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway, and down-regulating RIPK3 through the circRNA_0013936/miR-301b/CREB1 pathway in PMN-MDSCs. BCa-derived exosomal circRNA_0013936 promotes suppressive immunity by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway and down-regulating RIPK3 through the circRNA_0013936/miR-301b-3p/CREB1 pathway in PMN-MDSCs. These findings help to find new targets for clinical treatment of human bladder cancer.

中文翻译：

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膀胱癌来源的外泌体 circRNA_0013936 通过上调 PMN-MDSC 中的脂肪酸转运蛋白 2 和下调受体相互作用蛋白激酶 3 来促进抑制性免疫

多形核骨髓源性抑制细胞（PMN-MDSC）是肿瘤免疫耐受和癌症免疫治疗失败的原因之一。在这里，我们发现膀胱癌（BCa）来源的外泌体circRNA_0013936可以通过调节脂肪酸转运蛋白2（FATP2）和受体相互作用蛋白激酶3（RIPK3）的表达来增强PMN-MDSC的免疫抑制活性。然而，其根本机制仍然很大程度上未知。分离 BCa 衍生的外泌体并用于一系列实验。RNA测序用于鉴定差异表达的circRNA。通过Western blotting、免疫组化、免疫荧光、qRT-PCR、ELISA和流式细胞术揭示circRNA_0013936促进PMN-MDSC免疫抑制活性的潜在机制。富含BCa源性外泌体的CircRNA_0013936可以促进PMN-MDSC中FATP2的表达并抑制RIPK3的表达。从机制上讲，circRNA_0013936通过海绵miR-320a和miR-301b分别直接靶向JAK2和CREB1，促进FATP2的表达并抑制RIPK3的表达。最终，在 PMN-MDSC 中，circRNA_0013936 通过 circRNA_0013936/miR-320a/JAK2 通路上调 FATP2，并通过 circRNA_0013936/miR-301b/CREB1 通路下调 RIPK3，从而显着抑制 CD8+ T 细胞的功能。在 PMN-MDSC 中，BCa 来源的外泌体 circRNA_0013936 通过 circRNA_0013936/miR-320a/JAK2 途径上调 FATP2 并通过 circRNA_0013936/miR-301b-3p/CREB1 途径下调 RIPK3，从而促进抑制性免疫。这些发现有助于寻找人类膀胱癌临床治疗的新靶点。