期刊文献

The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer 收藏

TLR7 / 8激动剂R848重塑肿瘤和宿主反应以促进胰腺癌的生存

原文求助发布源

作者

Katherine A. Michaelis[1];Mason A. Norgard[2];Xinxia Zhu[2];Peter R. Levasseur[2];Shamilene Sivagnanam[3];Shannon M. Liudahl[4];Kevin G. Burfeind[1];Brennan Olson[1];Katherine R. Pelz[2];Diana M. Angeles Ramos[2];H. Carlo Maurer[5];Kenneth P. Olive[5];Lisa M. Coussens[4];Terry K. Morgan[6];Daniel L. Marks[7]

作者单位

[1]Medical Scientist Training Program, Oregon Health & Science University, Portland, USA;[2]Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, USA;[3]Department of Computational Biology, Oregon Health & Science University, Portland, USA;[4]Department of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, USA;[5]Departments of Medicine and Pathology and Cell Biology, Columbia University Medical Center, New York, USA;[6]Department of Pathology, Oregon Health & Science University, Portland, USA;[7]Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, USA

发布日期

15 October 2019

DOI

10.1038/s41467-019-12657-w

来源信息

Nature Communications ISSN：2041-1723, 2019年

摘要

A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8⁺ T-cell infiltration and activity, and decreased Treg frequency. R848-treated mice demonstrated improvements in behavioral and molecular cachexia manifestations, resulting in a near-doubling of survival duration. Knockout mouse studies revealed that stromal, not neoplastic, TLR7 is requisite for R848-mediated responses. In patient samples, we found Tlr7 is ubiquitously expressed in stroma across all stages of pancreatic neoplasia, but epithelial Tlr7 expression is relatively uncommon. These studies indicate immune-enhancing approaches including R848 may be useful in PDAC and cancer-associated cachexia.

摘要译文

癌症研究的重点是创新不仅可以有效对抗肿瘤进展的疗法，还可以解决诸如恶病质等限制生命质量和数量的合并症。我们证明了TLR7 / 8激动剂R848在胰腺导管腺癌（PDAC）小鼠模型中诱导抗肿瘤反应并减轻恶病质。在体内，来自三种细胞系中的两种的肿瘤对R848敏感，从而导致较小的肿瘤块，增加的免疫复杂性，增加的CD8 ^{+ T细胞浸润和活性以及降低的Treg频率。经R848处理的小鼠表现出行为和分子恶病质表现的改善，导致生存期延长了近一倍。剔除小鼠研究表明，基质细胞而非肿瘤细胞的TLR7是R848介导的反应所必需的。在患者样品中，我们发现在胰腺肿瘤的所有阶段中，Tlr7在基质中普遍表达，但上皮Tlr7表达相对罕见。这些研究表明，包括R848在内的免疫增强方法可能对PDAC和癌症相关的恶病质很有用。}