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 1 macrophages. CRC patients (n 5 271) (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 5 178), 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.

Prognostic significance of nomograms integrating IL‐37 expression, neutrophil level, and MMR status in patients with colorectal cancer

“…Furthermore, recent evidence shows that TANs are endowed with considerable plasticity basing on environmental cues. In CRC, the presence and significance of TANs have been the subjects of conflicting reports 20, 22, 24. In this present study, we set out to rigorously evaluate the prognostic significance of TANs in CRC.…”

“…In contrast, low TAN levels identified a subgroup of muscle invasive bladder cancer (MIBC) patients who appeared to benefit from adjuvant chemotherapy 16. In CRC patients, Galdiero et al22 revealed that a higher TAN density was associated with a better response to 5‐FU‐based chemotherapy. And this also indicates that neutrophils show different functions under different tumor microenvironments.…”

“…Many studies have found neutrophils to be an independent factor of poor prognosis and promote the growth of distance metastases in CRC 23, 24. However, other studies have revealed that tumor‐infiltrating neutrophils are associated with a better prognosis in CRC and might promote antitumor immunity 22, 25. CD66b was found to be a reliable marker to identify TANs in cancer tissues using immunohistochemistry, including in CRC tissues 17, 19, 22, 24, 26.…”

“…However, other studies have revealed that tumor‐infiltrating neutrophils are associated with a better prognosis in CRC and might promote antitumor immunity 22, 25. CD66b was found to be a reliable marker to identify TANs in cancer tissues using immunohistochemistry, including in CRC tissues 17, 19, 22, 24, 26. Thus, the prognostic role of TANs in CRC is not yet conclusive, and the relationship of IL‐37 and CD66b + TANs has not been previously elucidated.…”

“…Plasticity in neutrophils has recently been shown to lead to both pro‐ and antitumor effects 18. Therefore, the role of TANs in tumors remains controversial, including CRC 18, 19, 22. Many studies have found neutrophils to be an independent factor of poor prognosis and promote the growth of distance metastases in CRC 23, 24.…”