High Myeloperoxidase Positive Cell Infiltration in Colorectal Cancer Is an Independent Favorable Prognostic Factor

Abstract

BackgroundColorectal 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).MethodsA 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.ResultsMPO+ 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−.ConclusionsHigh density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC.

The Interplay Between Neutrophils and CD8+ T Cells Improves Survival in Human Colorectal Cancer

“…TMA slides were incubated with primary antibodies specific for CD8, CD16, MPO (18,22,23), and CD66b (clone G10F5, Biolegend). Secondary staining and negative controls were performed as described previously (18,22,23).…”

“…Secondary staining and negative controls were performed as described previously (18,22,23). Colorectal cancer infiltration by cells expressing defined markers was scored by experienced pathologists.…”

“…We previously observed that colorectal cancer infiltration by CD16 þ myeloid cells correlates with favorable outcome (22). Similarly to neutrophils, these cells are HLA-class II and largely myeloperoxidase (MPO)þ (23). Data from other groups suggest that high tumor infiltration by CD66b þ neutrophils may correlate with either benign or poor prognosis in patients with colorectal cancer.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Recently, a high myeloperoxidase (MPO) + CD15 + cell infiltration representing neutrophils in colorectal carcinoma was found to be an independent favorable prognostic factor [362,363]. Also, the increased presence of CD16 + (FcγRIII) myeloid cells of the monocyte/macrophage lineage that were also positive for CD45, CD33, CD11b, and CD11c, but not CD64 or HLA-DR, was found to be associated with improved survival in patients with colorectal carcinoma [364].…”

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

“…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.…”