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

Autor: Oweida AJ; Department of Nuclear Medicine and Radiobiology, University of Sherbrooke, Sherbrooke, Canada., Mueller AC; Thomas Jefferson University, Bodine Center for Cancer Treatment, 1665 Aurora Court Suite 1032, Philadelphia, PA, USA., Piper M; Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, CO, 80045, USA., Milner D; Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, CO, 80045, USA., Van Court B; Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, CO, 80045, USA., Bhatia S; Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, CO, 80045, USA., Phan A; Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, CO, 80045, USA., Bickett T; Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, CO, 80045, USA., Jordan K; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Proia T; Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Boston, MA, USA., Schulick R; Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Messersmith WA; Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Del Chiaro M; Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Clambey E; Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Gough MJ; Earle A. Chiles Research Institute, Providence Medical Center, Portland, OR, USA., Williams J; Department of Biochemistry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Hansen K; Department of Biochemistry, University of Colorado Anschutz Medical Campus, Aurora, CO, USA., Goodman K; Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Karam SD; Department of Nuclear Medicine and Radiobiology, University of Sherbrooke, Sherbrooke, Canada. sana.karam@cuanschutz.edu.; Department of Radiation Oncology, University of Colorado Anschutz Medical Campus, 1665 Aurora Court Suite 1032, Aurora, CO, 80045, USA. sana.karam@cuanschutz.edu.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2021 Apr; Vol. 70 (4), pp. 989-1000. Date of Electronic Publication: 2020 Oct 23.
DOI: 10.1007/s00262-020-02701-w
Abstrakt: 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.
Databáze: MEDLINE
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