Purpose

The transforming growth factor-beta (TGF-β) pathway plays a paradoxical, context-dependent role in pancreatic ductal adenocarcinoma (PDAC): a tumor-suppressive role in non-metastatic PDAC and a tumor-promotive role in metastatic PDAC. We hypothesize that non-SMAD-TGF-β signaling induces PDAC progression.

Methods

We investigated the expression of non-SMAD-TGF-β signaling proteins (pMAPK14, PD-L1, pAkt and c-Myc) in patient-derived tissues, cell lines and an immunocompetent mouse model. Experimental models were complemented by comparing the signaling proteins in PDAC specimens from patients with various survival intervals. We manipulated models with TGF-β, gemcitabine (DNA synthesis inhibitor), galunisertib (TGF-β receptor inhibitor) and MK-2206 (Akt inhibitor) to investigate their effects on NF-κB, β-catenin, c-Myc and PD-L1 expression. PD-L1 expression was also investigated in cancer cells and tumor associated macrophages (TAMs) in a mouse model.

Results

We found that tumors from patients with aggressive PDAC had higher levels of the non-SMAD-TGF-β signaling proteins pMAPK14, PD-L1, pAkt and c-Myc. In PDAC cells with high baseline β-catenin expression, TGF-β increased β-catenin expression while gemcitabine increased PD-L1 expression. Gemcitabine plus galunisertib decreased c-Myc and NF-κB expression, but induced PD-L1 expression in some cancer models. In mice, gemcitabine plus galunisertib treatment decreased metastases (p = 0.018), whereas galunisertib increased PD-L1 expression (p < 0.0001). In the mice, liver metastases contained more TAMs compared to the primary pancreatic tumors (p = 0.001), and TGF-β increased TAM PD-L1 expression (p < 0.05).

Conclusions

In PDAC, the non-SMAD-TGF-β signaling pathway leads to more aggressive phenotypes, TAM-induced immunosuppression and PD-L1 expression. The divergent effects of TGF-β ligand versus receptor inhibition in tumor cells versus TAMs may explain the TGF-β paradox. Further evaluation of each mechanism is expected to lead to the development of targeted therapies.

中文翻译：

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TGF-β 在胰腺导管腺癌进展和 PD-L1 表达中的作用

目的

转化生长因子-β (TGF-β) 通路在胰腺导管腺癌 (PDAC) 中发挥着自相矛盾的依赖性作用：在非转移性 PDAC 中具有肿瘤抑制作用，在转移性 PDAC 中具有肿瘤促进作用。我们假设非 SMAD-TGF-β 信号传导诱导 PDAC 进展。

方法

我们研究了非 SMAD-TGF-β 信号蛋白（pMAPK14、PD-L1、pAkt 和 c-Myc）在患者来源的组织、细胞系和免疫活性小鼠模型中的表达。通过比较不同生存期患者的 PDAC 标本中的信号蛋白来补充实验模型。我们使用 TGF-β、吉西他滨（DNA 合成抑制剂）、galunisertib（TGF-β 受体抑制剂）和 MK-2206（Akt 抑制剂）操纵模型，以研究它们对 NF-κB、β-连环蛋白、c-Myc 和 PD- L1表达。还在小鼠模型中的癌细胞和肿瘤相关巨噬细胞 (TAM) 中研究了 PD-L1 表达。

结果

我们发现来自侵袭性 PDAC 患者的肿瘤具有更高水平的非 SMAD-TGF-β 信号蛋白 pMAPK14、PD-L1、pAkt 和 c-Myc。在具有高基线 β-连环蛋白表达的 PDAC 细胞中，TGF-β 增加 β-连环蛋白表达，而吉西他滨增加 PD-L1 表达。吉西他滨联合 galunisertib 降低了 c-Myc 和 NF-κB 的表达，但在一些癌症模型中诱导了 PD-L1 的表达。在小鼠中，吉西他滨加 galunisertib 治疗减少了转移 ( p  = 0.018)，而 galunisertib 增加了 PD-L1 表达 ( p  < 0.0001)。在小鼠中，与原发性胰腺肿瘤相比，肝转移瘤含有更多的 TAM ( p  = 0.001)，并且 TGF-β 增加了 TAM PD-L1 的表达 ( p  < 0.05)。

结论

在 PDAC 中，非 SMAD-TGF-β 信号通路导致更具侵袭性的表型、TAM 诱导的免疫抑制和 PD-L1 表达。TGF-β 配体与受体抑制在肿瘤细胞和 TAM 中的不同作用可以解释 TGF-β 悖论。对每种机制的进一步评估有望导致靶向治疗的发展。