PDF(Pubmed)
Abstract：
The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph nodes (TDLNs), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G+ MDSCs in vivo. Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. In vitro, CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33+ MDSCs derived from human peripheral blood mononuclear cells. These results suggest a dual role for intra-tumorally injected CHST15 siRNA on modulating the tumor immune microenvironment for T cell entry and remotely diminishing CHST15+ MDSCs, decreasing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs.
摘要：
致密基质是T细胞介导的免疫疗法在胰腺导管腺癌（PDAC）中疗效不佳的原因之一。碳水化合物磺基转移酶15（CHST15）是一种蛋白聚糖合成酶，负责重塑肿瘤基质。CHST15小干扰RNA(siRNA)的肿瘤内注射已显示增加患有不可切除的PDAC的患者的肿瘤浸润性T细胞(TIL)。然而,TILs积累增强的潜在机制尚未完全探索。这里,我们证明,在小鼠体内局部和远程注射CHST15siRNA可减少髓源性抑制细胞(MDSC)并增强TIL.CHST15在肿瘤和肿瘤引流淋巴结（TDLN）中由肿瘤细胞和MDSCs表达，CHST15siRNA抑制基质密度，中性粒细胞胞外诱捕网，和体内Ly6C/G+MDSC。值得注意的是,肿瘤生长抑制仅在免疫活性KPC模型中观察到，它与增强的TIL相关联。体外，CHST15siRNA显著下调源自人外周血单核细胞的CD33+MDSCs中CHST15和吲哚胺2,3-双加氧酶mRNA的水平。这些结果表明，肿瘤内注射的CHST15siRNA在调节T细胞进入的肿瘤免疫微环境和远程减少CHST15+MDSCs方面具有双重作用。在TDLN中减少T细胞抑制和扩增T细胞，最终导致TIL的积累增加。
