Targeted inhibition in stromal TGFβ activity in pancreatic cancer

转化生长因子β(转化生长因子β)是治疗肿瘤的一个有吸引力的靶点。然而， 阻断转化生长因子β治疗胰腺癌的临床研究尚未取得成功。这是到期的 部分原因是转化生长因子β信号在一定程度上抑制胰腺癌细胞的生长- 依赖的态度。相反，基质细胞中的转化生长因子β信号促进肿瘤进展 通过诱导纤维化和免疫抑制，PDA的特点。此外，我们有 已鉴定的转化生长因子β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，与PDA相关的成纤维细胞产生IL-6会降低NK细胞的活性，从而促进 动脉导管未端转移。利用物种特异性工具，我们证明了对基质的选择性抑制 转化生长因子β信号转导减少荷瘤小鼠动脉导管的转移 上皮性肿瘤细胞表型和免疫微环境改变。这些观察结果 强烈提示转化生长因子β驱动的PDA间质细胞与肿瘤细胞之间存在旁分泌网络。 这会促进肿瘤的发展。高达60%的人PDA存在肿瘤细胞特异性缺陷 典型的转化生长因子β信号通过转化生长因子β受体2的缺失(转化生长因子βR2)或下游信号传递 调解人Smad4。在此，我们认为选择性抑制基质细胞转化生长因子β信号转导。 携带转化生长因子β信号上皮突变的PDA将显著且安全地增强 化疗和/或免疫治疗的疗效。描述涉及的机制并进行测试 这一新的策略，我们提出了以下目标：1，确定转化生长因子β信号在肿瘤相关 成纤维细胞推动动脉粥样硬化进展；2，确定基质转化生长因子β抑制对 化疗和关卡阻断对转化生长因子β突变型动脉导管未闭模型的疗效。如果经过验证 纠正这一点将提供一个对PDA患者进行分层的理论基础，以便那些具有肿瘤细胞的患者 转化生长因子β信号的突变可能是抑制间质转化生长因子β信号的候选因素 与标准疗法或免疫疗法相结合。

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.