Bone metastatic disease of prostate cancer (PCa) is incurable and progression in bone is largely dictated by tumor-stromal interactions in the bone microenvironment. We showed previously that bone neutrophils initially inhibit bone metastatic PCa growth yet metastatic PCa becomes resistant to neutrophil response. Further, neutrophils isolated from tumor-bone lost their ability to suppress tumor growth through unknown mechanisms. With this study, our goal was to define the impact of metastatic PCa on neutrophil function throughout tumor progression and to determine the potential of neutrophils as predictive biomarkers of metastatic disease. Using patient peripheral blood polymorphonuclear neutrophils (PMNs), we identified that PCa progression dictates PMN cell surface markers and gene expression, but not cytotoxicity against PCa. Importantly, we also identified a novel phenomenon in which second generation androgen deprivation therapy (ADT) suppresses PMN cytotoxicity via increased transforming growth factor beta receptor I (TβRI). High dose testosterone and genetic or pharmacologic TβRI inhibition rescued androgen receptor-mediated neutrophil suppression and restored neutrophil anti-tumor immune response. These studies highlight the ability to leverage standard-care ADT to generate neutrophil anti-tumor responses against bone metastatic PCa.
Cancer letters. 2023 Nov 07 [Epub ahead of print]
Massar Alsamraae, Diane Costanzo-Garvey, Benjamin A Teply, Shawna Boyle, Gary Sommerville, Zachary T Herbert, Colm Morrissey, Alicia J Dafferner, Maher Y Abdalla, Rachel W Fallet, Tammy Kielian, Heather Jensen-Smith, Edson I deOliveira, Keqiang Chen, Ian A Bettencourt, Ji Ming Wang, Daniel W McVicar, Tyler Keeley, Fang Yu, Leah M Cook
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA., Fred & Pamela Buffett Cancer Center, Omaha, NE, USA; Division of Oncology & Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center Omaha, NE, USA., Fred & Pamela Buffett Cancer Center, Omaha, NE, USA., Dana Farber Cancer Institute, Boston, MA, USA., University of Washington, Seattle, WA, USA., Fred & Pamela Buffett Cancer Center, Omaha, NE, USA; Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, USA., Laboratory of Cancer Innovation, National Cancer Institute, Frederick, MD, USA., Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA., Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Fred & Pamela Buffett Cancer Center, Omaha, NE, USA. Electronic address: .