Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 69, Issue 6, Pages 1113-1130Publisher
SPRINGER
DOI: 10.1007/s00262-020-02527-6
Keywords
Neutrophils; Bone; Metastasis; Prostate; Cancer; STAT5
Categories
Funding
- American Cancer Society [PF-13-17501-CSM, RSG-19-127-01-CSM]
- National Institute of Health [R00HL123471]
- National Institutes of Health/National Institute of Allergy and Infectious Disease Grant [P01 AI083211]
- Flow Cytometry at the H. Lee Moffitt Cancer Center and Research Institute - Moffitt's Cancer Center Support Grant [P30-CA076292]
- Small Animal Imaging Laboratory at the H. Lee Moffitt Cancer Center and Research Institute - Moffitt's Cancer Center Support Grant [P30-CA076292]
- Microscopy cores at the H. Lee Moffitt Cancer Center and Research Institute - Moffitt's Cancer Center Support Grant [P30-CA076292]
- Pacific Northwest Prostate Cancer SPORE [P50CA97186]
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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.
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