Neutrophils are mediators of metastatic prostate cancer progression in bone

• Published in: Cancer Immunology, Immunotherapy Vol. 69; no. 6; pp. 1113 - 1130
• Main Authors: Costanzo-Garvey, Diane L., Keeley, Tyler, Case, Adam J., Watson, Gabrielle F., Alsamraae, Massar, Yu, Yangsheng, Su, Kaihong, Heim, Cortney E., Kielian, Tammy, Morrissey, Colm, Frieling, Jeremy S., Cook, Leah M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2020; Springer Nature B.V
• Subjects: Animals; Apoptosis; Bone cancer; Bone growth; Bone lesions; Bone marrow; Bone Neoplasms - secondary; Bone tumors; Cancer Research; Cell Line, Tumor; Cytotoxicity; Disease Models, Animal; Disease Progression; Humans; Immunology; Immunotherapy; Leukocytes (neutrophilic); Male; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Neutrophils; Neutrophils - cytology; Neutrophils - metabolism; Oncology; Original; Original Article; Prostate cancer; Prostatic Neoplasms - blood; Prostatic Neoplasms - complications; Prostatic Neoplasms - pathology; Stat5 protein; STAT5; Bone; Metastasis; Prostate; Neutrophils; Cancer
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-020-02527-6

Bone metastatic prostate cancer (BM-PCa) significantly reduces overall patient survival and is currently incurable. Current standard immunotherapy showed promising results for PCa patients with metastatic, but less advanced, disease (i.e., fewer than 20 bone lesions) suggesting that PCa growth in bone contributes to response to immunotherapy. We found that: (1) PCa stimulates recruitment of neutrophils, the most abundant immune cell in bone, and (2) that neutrophils heavily infiltrate regions of prostate tumor in bone of BM-PCa patients. Based on these findings, we examined the impact of direct neutrophil–prostate cancer interactions on prostate cancer growth. Bone marrow neutrophils directly induced apoptosis of PCa in vitro and in vivo, such that neutrophil depletion in bone metastasis models enhanced BM-PCa growth. Neutrophil-mediated PCa killing was found to be mediated by suppression of STAT5, a transcription factor shown to promote PCa progression. However, as the tumor progressed in bone over time, neutrophils from late-stage bone tumors failed to elicit cytotoxic effector responses to PCa. These findings are the first to demonstrate that bone-resident neutrophils inhibit PCa and that BM-PCa are able to progress via evasion of neutrophil-mediated killing. Enhancing neutrophil cytotoxicity in bone may present a novel therapeutic option for bone metastatic prostate cancer.