PURPOSE Metastasis remains a major hurdle in treating aggressive malignancies such as pancreatic ductal adenocarcinoma (PDAC). Improving response to treatment, therefore, requires a more detailed characterization of the cellular populations involved in controlling metastatic burden. EXPERIMENTAL DESIGN PDAC patient tissue samples were subjected to RNA sequencing analysis to identify changes in immune infiltration following radiotherapy. Genetically engineered mouse strains in combination with orthotopic tumor models of PDAC were used to characterize disease progression. Flow cytometry was used to analyze tumor infiltrating, circulating, and nodal immune populations. RESULTS We demonstrate that although radiotherapy increases the infiltration and activation of dendritic cells (DC), it also increases the infiltration of regulatory T cells (Treg) while failing to recruit natural killer (NK) and CD8 T cells in PDAC patient tissue samples. In murine orthotopic tumor models, we show that genetic and pharmacologic depletion of Tregs and NK cells enhances and attenuates response to radiotherapy, respectively. We further demonstrate that targeted inhibition of STAT3 on Tregs results in improved control of local and distant disease progression and enhanced NK-mediated immunosurveillance of metastasis. Moreover, combination treatment of STAT3 antisense oligonucleotide (ASO) and radiotherapy invigorated systemic immune activation and conferred a survival advantage in orthotopic and metastatic tumor models. Finally, we show the response to STAT3 ASO + radiotherapy treatment is dependent on NK and DC subsets. CONCLUSIONS Our results suggest targeting Treg-mediated immunosuppression is a critical step in mediating a response to treatment, and identifying NK cells as not only a prognostic marker of improved survival, but also as an effector population that functions to combat metastasis.

中文翻译：

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靶向 Treg 表达的 STAT3 可增强 NK 介导的转移监测并改善胰腺癌的治疗反应。


目的 转移仍然是治疗胰腺导管腺癌 (PDAC) 等侵袭性恶性肿瘤的主要障碍。因此，改善治疗反应需要对参与控制转移负担的细胞群进行更详细的表征。实验设计 对 PDAC 患者组织样本进行 RNA 测序分析，以确定放疗后免疫浸润的变化。基因工程小鼠品系与 PDAC 原位肿瘤模型相结合，用于表征疾病进展。流式细胞术用于分析肿瘤浸润、循环和淋巴结免疫群体。结果我们证明，虽然放疗增加了树突状细胞 (DC) 的浸润和活化，但它也增加了调节性 T 细胞 (Treg) 的浸润，同时无法在 PDAC 患者组织样本中招募自然杀伤 (NK) 和 CD8 T 细胞。在小鼠原位肿瘤模型中，我们发现 Tregs 和 NK 细胞的遗传和药理学耗竭分别增强和减弱对放射治疗的反应。我们进一步证明，靶向抑制 Tregs 上的 STAT3 可以改善对局部和远处疾病进展的控制，并增强 NK 介导的转移免疫监视。此外，STAT3反义寡核苷酸（ASO）和放疗的联合治疗可增强全身免疫激活，并在原位和转移性肿瘤模型中赋予生存优势。最后，我们表明对 STAT3 ASO + 放射治疗的反应取决于 NK 和 DC 亚群。 结论 我们的结果表明，针对 Treg 介导的免疫抑制是介导治疗反应的关键步骤，并且将 NK 细胞鉴定为不仅是改善生存的预后标志物，而且还是对抗转移的效应细胞群。