title: Occurrence and significance of tumor-associated neutrophils in patients with colorectal cancer.
abstract: Inflammatory cells are an essential component of the tumor microenvironment. Neutrophils have emerged as important players in the orchestration and effector phase of innate and adaptive immunity. The significance of tumor-associated neutrophils (TAN) in colorectal cancer (CRC) has been the subject of conflicting reports and the present study was designed to set up a reliable methodology to assess TAN infiltration in CRC and to evaluate their clinical significance. CD66b and myeloperoxidase (MPO) were assessed as candidate neutrophil markers in CRC using immunohistochemistry. CD66b was found to be a reliable marker to identify TAN in CRC tissues, whereas MPO also identified a subset of CD68(+) macrophages. CRC patients (n = 271) (Stages I-IV) were investigated retrospectively by computer-assisted imaging on whole tumor sections. TAN density dramatically decreases in Stage IV patients as compared to Stage I-III. At Cox analysis, higher TAN density was associated with better prognosis. Importantly, multivariate analysis showed that prognostic significance of TAN can be influenced by clinical stage and 5-fluorouracil(5-FU)-based chemotherapy. On separate analysis of Stage III patients (n = 178), TAN density had a dual clinical significance depending on the use of 5-FU-based chemotherapy. Unexpectedly, higher TAN density was associated with better response to 5-FU-based chemotherapy. Thus, TAN are an important component of the immune cell infiltrate in CRC and assessment of TAN infiltration may help identify patients likely to benefit from 5-FU-based chemotherapy. These results call for a reassessment of the role of neutrophils in cancer using rigorous quantitative methodology.
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.|Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Galdiero
authors.affiliation: Molecular Gastroenterology, Department of Gastroenterology & Clinical Investigation Laboratory, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bianchi
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grizzi
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Di Caro
authors.affiliation: Molecular Gastroenterology, Department of Gastroenterology & Clinical Investigation Laboratory, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ponzetta
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bonavita
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Barbagallo
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tartari
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Polentarutti
authors.affiliation: Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.|Department of Biotechnologies and Translational Medicine, University of Milan, Rozzano, Milan, 20089, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.affiliation: Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Marone
authors.affiliation: Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.|Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, 20089, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Roncalli
authors.affiliation: Hereditary Cancer Genetic Clinic & Molecular Gastroenterology, Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan 20089, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Laghi
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.|Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, 20089, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.|Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, 20089, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.affiliation: Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Milan, 20089, Italy.|Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, 20089, Italy.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jaillon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009367:Neoplasm Staging; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; C117307:KRAS protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: colorectal cancer; innate immunity; neutrophils; predictive markers; prognosis