Targeted inhibition in stromal TGFβ activity in pancreatic cancer

转化生长因子β（Transforming growth factor β，TGFβ）是肿瘤治疗的重要靶点。然而，在这方面， 在胰腺癌（PDA）中阻断TGFβ在临床研究中尚未成功。这是由于 部分原因是TGFβ信号传导抑制胰腺癌细胞生长， 依赖的方式。相反，基质细胞中的TGFβ信号促进肿瘤进展 通过诱导纤维化和免疫抑制，PDA的特征。而且我们 鉴定的TGFβ刺激的成纤维细胞产生限制先天免疫细胞活性的细胞因子。为 例如，PDA相关成纤维细胞产生的IL-6降低了NK细胞活性， PDA转移。使用物种特异性工具，我们证明了选择性抑制间质 TGFβ信号转导减少携带PDA异种移植物的小鼠中的PDA转移，并且还促进肿瘤细胞的增殖。 上皮肿瘤细胞表型和改变的免疫微环境。这些观察结果 强烈提示PDA中基质细胞和肿瘤细胞之间存在TGFβ驱动旁分泌网络 促进肿瘤进展的基因高达60%的人PDA具有肿瘤细胞特异性缺陷， 通过TGFβ受体2（TGFβR2）或下游信号丢失的典型TGFβ信号传导 介体SMAD 4。在这里，我们提出选择性抑制间质细胞中的TGFβ信号转导， 携带TGFβ信号传导中上皮突变的PDA将显著且安全地增强 化疗和/或免疫治疗的功效。为了描述所涉及的机制并测试 针对这一新的策略，我们提出了以下目标：1、鉴定肿瘤相关的TGFβ信号通路 2.确定间质TGFβ抑制对PDA进展的影响， TGFβ突变型PDA模型中化疗和检查点阻断的有效性。如果证明 纠正这一点将为PDA患者分层提供理论基础， TGFβ信号传导中的突变可能是抑制间质TGFβ信号传导的候选者， 与标准疗法或免疫疗法组合。

Transforming growth factor β (TGFβ) is an attractive therapeutic target in cancer. However, blocking TGFβ in pancreatic cancer (PDA) has not been successful in clinical studies. This is due part to the fact that TGFβ signaling suppresses pancreatic cancer cell growth in a context- dependent manner. In contrast, TGFβ signaling in stromal cells promotes to tumor progression by inducing fibrosis and immunosuppression, characteristics of PDA. Moreover, we have identified TGFβ-stimulated fibroblasts produce cytokines that limit innate immune cell activity. For example, IL-6 production by PDA associated fibroblasts reduces NK cell activity that facilitates PDA metastasis. Using species specific tools we demonstrated that selective inhibition of stromal TGFβ signaling reduces PDA metastasis in mice bearing PDA xenografts and also promotes an epithelial tumor cell phenotype and an altered immune microenvironment. These observations strongly suggest a TGFβ-driven paracrine network between stromal cells and tumor cells in PDA that promotes tumor progression. Up to 60% of human PDA have tumor cell specific deficiency in canonical TGFβ signaling via loss of TGFβ receptor 2 (TGFβR2) or the downstream signal mediator SMAD4. Here we propose that selective inhibition of TGFβ signaling in stromal cells in PDA that harbors epithelial mutations in TGFβ signaling will dramatically and safely enhance the efficacy of chemotherapy and/or immune therapy. To delineate the mechanisms involved and test this novel strategy, we propose the following aims: 1, Identify TGFβ signaling in cancer associated fibroblasts that drive PDA progression; 2, Determine the effect of stromal TGFβ inhibition on the efficacy of chemotherapy and checkpoint blockade in models of TGFβ mutant PDA. If proven correct this would provide a rationale to stratify PDA patients such that those with tumor cell mutations in TGFβ signaling would be candidates for inhibition of stromal TGFβ signaling in combination with standard therapy or immune therapy.