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

Katherine A. Michaelis, Mason A. Norgard, Xinxia Zhu, Peter R. Levasseur, Shamilene Sivagnanam, Shannon M. Liudahl, Kevin G. Burfeind, Brennan Olson, Katherine R. Pelz, Diana M. Angeles Ramos, H. Carlo Maurer, Kenneth P. Olive, Lisa M. Coussens, Terry K. Morgan, Daniel L. Marks

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number4682
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

resiquimod
Pancreatic Neoplasms
Tumors
tumors
cancer
Cachexia
Survival
Neoplasms
knockout mice
T-cells
infiltration
cultured cells
Infiltration
progressions
Adenocarcinoma
mice
therapy
Cells
Knockout Mice
Comorbidity

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer. / Michaelis, Katherine A.; Norgard, Mason A.; Zhu, Xinxia; Levasseur, Peter R.; Sivagnanam, Shamilene; Liudahl, Shannon M.; Burfeind, Kevin G.; Olson, Brennan; Pelz, Katherine R.; Angeles Ramos, Diana M.; Maurer, H. Carlo; Olive, Kenneth P.; Coussens, Lisa M.; Morgan, Terry K.; Marks, Daniel L.

In: Nature communications, Vol. 10, No. 1, 4682, 01.12.2019.

Research output: Contribution to journalArticle

Michaelis, KA, Norgard, MA, Zhu, X, Levasseur, PR, Sivagnanam, S, Liudahl, SM, Burfeind, KG, Olson, B, Pelz, KR, Angeles Ramos, DM, Maurer, HC, Olive, KP, Coussens, LM, Morgan, TK & Marks, DL 2019, 'The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer', Nature communications, vol. 10, no. 1, 4682. https://doi.org/10.1038/s41467-019-12657-w
Michaelis, Katherine A. ; Norgard, Mason A. ; Zhu, Xinxia ; Levasseur, Peter R. ; Sivagnanam, Shamilene ; Liudahl, Shannon M. ; Burfeind, Kevin G. ; Olson, Brennan ; Pelz, Katherine R. ; Angeles Ramos, Diana M. ; Maurer, H. Carlo ; Olive, Kenneth P. ; Coussens, Lisa M. ; Morgan, Terry K. ; Marks, Daniel L. / The TLR7/8 agonist R848 remodels tumor and host responses to promote survival in pancreatic cancer. In: Nature communications. 2019 ; Vol. 10, No. 1.
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