Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid-derived suppressor cells using STAT3 anti-sense oligonucleotide

Ayman J. Oweida, Adam C. Mueller, Miles Piper, Dallin Milner, Benjamin Van Court, Shilpa Bhatia, Andy Phan, Thomas Bickett, Kimberly Jordan, Theresa Proia, Richard Schulick, Wells A. Messersmith, Marco Del Chiaro, Eric Clambey, Michael J. Gough, Jason Williams, Kirk Hansen, Karyn Goodman, Sana D. Karam

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a heterogeneous tumor microenvironment (TME) comprised of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, neutrophils, regulatory T cells, and myofibroblasts. The precise mechanisms that regulate the composition of the TME and how they contribute to radiotherapy (RT) response remain poorly understood. In this study, we analyze changes in immune cell populations and circulating chemokines in patient samples and animal models of pancreatic cancer to characterize the immune response to radiotherapy. Further, we identify STAT3 as a key mediator of immunosuppression post-RT. We found granulocytic MDSCs (G-MDSCs) and neutrophils to be increased in response to RT in murine and human PDAC samples. We also found that RT-induced STAT3 phosphorylation correlated with increased MDSC infiltration and proliferation. Targeting STAT3 using an anti-sense oligonucleotide in combination with RT circumvented RT-induced MDSC infiltration, enhanced the proportion of effector T cells, and improved response to RT. In addition, STAT3 inhibition contributed to the remodeling of the PDAC extracellular matrix when combined with RT, resulting in decreased collagen deposition and fibrotic tissue formation. Collectively, our data provide evidence that targeting STAT3 in combination with RT can mitigate the pro-tumorigenic effects of RT and improve tumor response.

Original languageEnglish
Pages (from-to)989-1000
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume70
Issue number4
DOIs
StatePublished - Apr 2021

Keywords

  • Immunosuppression
  • Immunotherapy
  • Myeloid-derived suppressor cells
  • Pancreatic adenocarcinoma
  • Radiotherapy

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