Role of tumor‐associated macrophages at the invasive front in human colorectal cancer progression

Abstract

Macrophages are an essential component of antitumor activity; however, the role of tumor‐associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM‐CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM‐CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM‐CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan‐, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.

Interleukin-4 Programmed Macrophages Suppress Colitis and Do Not Enhance Infectious-Colitis, Inflammation-Associated Colon Cancer or Airway Hypersensitivity

“…Macrophage association with tumors is well documented, and whether described as TAMs, AAM or M2cells, the immunosuppressive nature of these cells via cognate ligands or the release of soluble signals has been linked to tumor progression by suppression of anti-tumor immunity (44). For example, the number of M2-macrophages, identified as CD68 + CD163 + cells on tissue sections, correlated with the progression and invasion of CRC (45). So while the link with immunosuppressive macrophages and CRC is not disputed, these cells are not identical to in vitro differentiated M(IL4)s; yet, the similarity between M(IL4)s and TAMs [e.g.…”

Targeting Metastatic Colorectal Cancer with Immune Oncological Therapies

“…By comparison, M2 macrophages occur through exposure to IL-4 or IL-13 and are thought to be more tumourigenic. In later stages, tumour-associated macrophages (TAMs) tend to polarise towards an M2 phenotype which secrete IL-10 and TGF beta, promoting immunosuppression, impairing T cells and influencing the tumour microenvironment (TME) through angiogenesis (such as VEGF) and the extracellular matrix (such as through MMP9) [ 38 ]. Sites of metastases secrete CCL2 which attracts circulating monocytes to the metastatic tumour deposit.…”

“…New targets for therapy continue to be identified via ongoing translational research to identify underpinning molecular mechanisms of immunopathology. Macrophages within the tumour microenvironment have been identified as key players in tumour progression, where an M2 phenotype creates resistance to anti-PD-1/PD-L1 agents [ 38 ]. In preclinical models, CSF1 receptor blockade has been effective in polarisation to M1 macrophages and restoring effective immune checkpoint immunotherapy.…”

Stage I–IV Colorectal Cancer Prognosis Can Be Predicted by Type and Number of Intratumoral Macrophages and CLEVER-1+ Vessel Density

“…The prognostic significance of TAMs has been studied in several human cancer types, and according to previous reports, a high density of TAMs predicts poor patient survival in many cancers [ 24 , 25 , 26 , 27 , 28 ]. In CRC, contradictory results regarding the prognostic role of TAMs have been reported [ 16 , 19 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ], Table 1 .…”