Furthermore, the capacity of granulocytes to undergo TGF-�� dependent polarization into N1 and N2 functional profiles, characterized by anti- or pro-tumoral properties, respectively, similarly to macrophages, has also been documented [20]. The molecular background underlying citation CRC infiltration by MPO+ cells and its prognostic significance is unclear. These phenomena could reflect chemokine production by activated T cells, and therefore indirectly result from ongoing antitumoral adaptive responses. Alternatively, they might be related to the production of granulocyte attracting chemokines by tumor cells. At least CXCL8 (IL-8) is known to be produced by CRC cells. However, its production was suggested to be associated with increased angiogenesis and tumor dissemination [72].
On the other hand, we and others have previously shown that GM-CSF, promoting granulocyte maturation and survival, can also be produced by CRC cells [73], [74]. Our results contribute to the characterization of the complex features inherent in gut microenvironment and with CRC-immune system interaction [75]. Further research is warranted to clarify molecular mechanisms underlying the independent prognostic impact of MPO+ cells in CRC. Importantly, here we show that CRC infiltrating MPO+ cells express CD16 Fc�� intermediate affinity receptor. The ability of granulocytes to mediate antibody dependent cellular cytotoxicity (ADCC) is debated. However, the availability of novel therapeutic mAb with glycoengineered Fc fragments characterized by increased affinity for Fc�� receptors [76] might lead to a reevaluation of the effector significance of granulocytes.
Within this framework, it is tempting to speculate that neutrophil infiltration should be included in current prognostic models for CRC [77] and that it might represent an important novel stratification factor for randomization in specific clinical trials. Funding Statement 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 Dacomitinib 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.
AIM: To analyze the expression of 8 putative cancer stem cell (CSC) markers within colorectal cancer tumor buds and to determine their prognostic impact in patients with this disease.