Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid-derived suppressor cel
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ORIGINAL ARTICLE
Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid‑derived suppressor cells using STAT3 anti‑sense oligonucleotide Ayman J. Oweida1 · Adam C. Mueller11 · Miles Piper10 · Dallin Milner10 · Benjamin Van Court10 · Shilpa Bhatia10 · Andy Phan10 · Thomas Bickett10 · Kimberly Jordan9 · Theresa Proia2 · Richard Schulick3 · Wells A. Messersmith4 · Marco Del Chiaro3 · Eric Clambey5 · Michael J. Gough6 · Jason Williams7 · Kirk Hansen7 · Karyn Goodman8 · Sana D. Karam1,10 Received: 21 May 2020 / Accepted: 14 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Pancreatic ductal adenocarcinoma (PDAC) has a heterogeneous tumor microenvironment (TME) comprised of myeloidderived 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. Keywords Immunotherapy · Radiotherapy · Pancreatic adenocarcinoma · Immunosuppression · Myeloid-derived suppressor cells
Introduction Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the world [1] with a dismal 5-year overall survival (OS) rate of 8% [2]. Approximately 30% of PDAC patients present with locally advanced (LA) disease and are deemed inoperable. Limited targeted therapies are available for LA-PDAC patients [3] and response to single-agent immunotherapy has been Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02701-w) contains supplementary material, which is available to authorized users. * Sana D. Karam [email protected] Extended author information available on the last page of the article
disappointing with new combinatorial approaches yet to show benefit [4]. Therefore, non-surgical approaches are limited to chemotherapy and radiotherapy (RT). Altho
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