Neutrophils wield an arsenal of cytotoxic agents, yet are largely believed to foster cancer development. While the literature has provided hints that neutrophils can oppose tumorigenesis, the models used in these studies required therapeutic manipulations to recruit artificially high numbers of neutrophils, and frequently implicated adaptive immune cells as the principal combatants of tumorigenesis. Whether neutrophils can endogenously and directly fight cancer, independently of assistance from other leukocytes, remains unknown. Using a mouse model of PTEN-deficient uterine cancer, we describe a surprising inhibitory role for neutrophils in epithelial carcinogenesis. Tumors recruited large numbers of neutrophils during early stages of progression, which induced a dramatic morphologic shift and a delay in tumor growth. Rather than impacting on tumor cell proliferation or death, neutrophils instead induced epithelial sloughing as they transmigrated through the neoplastic epithelium, thereby reducing tumor burden and ultimately impeding malignant progression. Extending our findings to human cancer, a gene signature representative of high intratumoral neutrophil numbers exhibited strong positive correlation with survival outcome in several cancer subtypes, including PTEN-deficient uterine cancer. Remarkably, other tumor-associated leukocytes were dispensable for neutrophil recruitment and anti-tumor effector function. Furthermore, cellular senescence, while previously implicated as a trigger of inflammation in PTEN-deficient tumors, played no role in our uterine cancer model. Instead, STAT3 signaling promoted inflammation via induction of neutrophil chemoattractants within tumor cells. Additionally, early neutrophil recruitment strongly correlated with the onset of a hypoxia-induced tumor cell-autonomous inflammatory response. These findings grant novel insight into tumor-associated neutrophils and reveal a context-specific capacity for neutrophils to directly combat tumorigenesis, thereby supporting efforts to harness these leukocytes therapeutically as endogenous anti-cancer agents.
|Commitee:||Bhardwaj, Nina, Ernst, Joel, Frey, Alan, Levy, David E.|
|School:||New York University|
|Department:||Basic Medical Science|
|School Location:||United States -- New York|
|Source:||DAI-B 77/05(E), Dissertation Abstracts International|
|Subjects:||Medicine, Immunology, Oncology|
|Keywords:||Cancer, Hypoxia, Inflammation, Neutrophil, Stat3, Uterus|
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