Purpose

Immunotherapy, such as checkpoint inhibitors against anti-programmed death-ligand 1 (PD-L1), has not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and the TGF-β cytokine are critical in anti-cancer immunity. We hypothesized that TGF-β enhances the immunosuppressive effects of TAM, MDSC, and DC presence in tumors.

Methods

Using a murine PDAC cell line derived from a genetically engineered mouse model, we orthotopically implanted treated cells plus drug embedded in Matrigel into immunocompetent mice. Treatments included saline control, TGF-β1, or a TGF-β receptor 1 small molecule inhibitor, galunisertib. We investigated TAM, MDSC, DC, and TAM PD-L1 expression with flow cytometry in tumors. Separately, we used the TIMER2.0 database to analyze TAM and PD-L1 gene expression in human PDAC tumors in TCGA database.

Results

TGF-β did not alter MDSC or DC frequencies in the primary tumors. However, in PDAC metastases to the liver, TGF-β decreased the proportion of MDSCs (P=0.022) and DCs (P=0.005). TGF-β significantly increased the percent of high PD-L1 expressing TAMs (32 ± 6 % vs. 12 ± 5%, P=0.013) but not the proportion of TAMs in primary and metastatic tumors. TAM PD-L1 gene expression in TCGA PDAC database was significantly correlated with tgb1 and tgfbr1 gene expression (P<0.01).

Conclusions

TGF-β is important in PDAC anti-tumor immunity, demonstrating context-dependent impact on immune cells. TGF-β has an overall immunosuppressive effect mediated by TAM PD-L1 expression and decreased presence of DCs. Future investigations will focus on enhancing anti-cancer immune effects of TGF-β receptor inhibition.

中文翻译：

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TGF-β 改变胰腺导管腺癌中浸润免疫细胞的比例

 目的

免疫疗法，例如抗程序性死亡配体 1 (PD-L1) 的检查点抑制剂，尚未成功治疗胰腺导管腺癌 (PDAC) 患者。肿瘤相关巨噬细胞 (TAM)、骨髓源性抑制细胞 (MDSC)、树突状细胞 (DC) 和 TGF-β 细胞因子在抗癌免疫中至关重要。我们假设 TGF-β 增强肿瘤中 TAM、MDSC 和 DC 的免疫抑制作用。

 方法

使用源自基因工程小鼠模型的小鼠 PDAC 细胞系，我们将处理过的细胞和嵌入基质胶中的药物原位植入免疫活性小鼠体内。治疗包括盐水对照、TGF-β1 或 TGF-β 受体 1 小分子抑制剂 galunisertib。我们通过流式细胞术研究了肿瘤中 TAM、MDSC、DC 和 TAM PD-L1 的表达。另外，我们使用TIMER2.0数据库分析TCGA数据库中人类PDAC肿瘤中TAM和PD-L1基因的表达。

 结果

TGF-β 不会改变原发肿瘤中的 MDSC 或 DC 频率。然而，在PDAC肝转移中，TGF-β降低了MDSCs（ P =0.022）和DCs（ P =0.005）的比例。 TGF-β 显着增加了高 PD-L1 表达 TAM 的百分比（32 ± 6 % vs. 12 ± 5%， P = 0.013），但不增加原发性和转移性肿瘤中 TAM 的比例。 TCGA PDAC 数据库中 TAM PD-L1 基因表达量与tgb1 、 tgfbr1基因表达量显着相关（ P <0.01）。

 结论

TGF-β 在 PDAC 抗肿瘤免疫中很重要，显示出对免疫细胞的环境依赖性影响。 TGF-β 具有由 TAM PD-L1 表达和 DC 存在减少介导的整体免疫抑制作用。未来的研究将集中于增强TGF-β受体抑制的抗癌免疫作用。