Abstract
Background:
Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG).
Methods:
A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets.
Results:
MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:±0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO-.
Conclusions:
High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation, Myelomonocytic / immunology
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Antigens, Differentiation, Myelomonocytic / metabolism
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Cell Adhesion Molecules / immunology
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Cell Adhesion Molecules / metabolism
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Colorectal Neoplasms / immunology*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Female
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Flow Cytometry
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Fucosyltransferases / immunology*
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Fucosyltransferases / metabolism
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GPI-Linked Proteins / immunology
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GPI-Linked Proteins / metabolism
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Humans
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Immunohistochemistry
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Lewis X Antigen / immunology*
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Lewis X Antigen / metabolism
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Male
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Middle Aged
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Multivariate Analysis
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Neoplasm Grading
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Neoplasm Staging
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Neutrophils / immunology*
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Neutrophils / metabolism
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Neutrophils / pathology
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Peroxidase / immunology*
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Peroxidase / metabolism
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Prognosis
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Receptors, IgG / immunology
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Receptors, IgG / metabolism
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Survival Analysis
Substances
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Antigens, CD
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Antigens, Differentiation, Myelomonocytic
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CD68 antigen, human
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CEACAM8 protein, human
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Cell Adhesion Molecules
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FCGR3B protein, human
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GPI-Linked Proteins
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Lewis X Antigen
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Receptors, IgG
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Peroxidase
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FUT4 protein, human
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Fucosyltransferases
Grants and funding
Financial support for this study was provided by the Swiss National Science Foundation (SNF) Grants Nr. PP00P3-133699, Nr. 31003A-122235 and Nr. 320030-120320, the Italian Association for Cancer Research (AIRC) IG Grant Nr. 10555, the Rainbow Association for Research in Pediatric Oncology-Hematology/The NANDO PERETTI Foundation, and Lazio Regional Agency for Transplantation and Related Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.