Galdiero, Maria Rosaria (2015) Clinical significance and functional roles of tumor-associated neutrophils in colorectal cancer. [Tesi di dottorato]

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Immune cells actively take part to the tumor microenvironment, where they play several roles in the multistep process of carcinogenesis. Among the tumor-infiltrating immune cells, myeloid cells represent a "double-edged sword" for cancer. Indeed, they can both promote or inhibit cancer initiation and progression. Neutrophils have long been viewed as short-lived cells, pivotal for the elimination of extracellular pathogens, with a limited role in the orchestration of the immune response. However, recent lines of evidence have challenged this limited point of view, revealing a number of unexpected functions for neutrophils in several pathological contexts. Indeed, neutrophils were also found among inflammatory cells infiltrating cancer tissues, such as colorectal cancer (CRC). Today, the functional roles of neutrophils in cancer and the association between neutrophil infiltration, clinicopathological features and outcome of CRC patients remain to be clarified. Here, we found that neutrophils are recruited within CRC tissues through a spatiotemporal dynamism. Infiltration of neutrophils increased from stage I to stage III CRC and decreased at stage IV. In a large cohort of stage III CRC, neutrophil infiltration was preferentially found in the intratumoral compartment compared with the invasive margin. Higher density of neutrophils within the tumor was found to be an independent prognostic factor for better patients' outcome (n=128, Stage I-Stage IV CRC) and a predictive factor for 5-FluoroUracyle chemotherapy response in Stage III CRC patients (n=178). Moreover, CRC cell lines released soluble factors, which promoted neutrophil chemotaxis and survival. In turn, neutrophils displayed a cytostatic activity towards CRC cell lines. Our data suggest that neutrophils are critical components of antitumor immunity and that neutrophil infiltration within tumors could be a useful predictive marker to identify patients with cancer who would likely benefit from chemotherapy. Therefore, neutrophils have to be considered as central participants in the regulation of the innate and adaptive immune responses, with important roles in the resolution or exacerbation of various pathologies, including cancer.

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