M2 tumor‑associated macrophages promote tumor progression in non‑small‑cell lung cancer

Abstract

Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment that can be polarized into different phenotypes, including tumor-inhibiting M1 macrophages and tumor-promoting M2 macrophages. To elucidate the biological and clinical significance of M2 TAMs in non-small-cell lung cancer (NSCLC), a comprehensive clinical assessment of the tissue distribution of M2 TAMs was performed. The tissue distribution of M2 TAMs was retrospectively analyzed using CD163 immunohistochemistry in 160 consecutive patients who underwent NSCLC resection. Tumor proliferation was evaluated via the Ki-67 proliferation index. The results revealed that the stromal density of M2 TAMs was significantly associated with the C-reactive protein (CRP) level (P=0.0250), the Ki-67 proliferation index (P=0.0090) and invasive size (P=0.0285). Furthermore, the stromal M2 TAM density was significantly associated with tumor differentiation (P=0.0018), lymph node metastasis (P=0.0347) and pathological stage (P=0.0412). The alveolar M2 TAM density was also significantly associated with the CRP level (P= 0.0309), invasive size (P<0.0001), tumor differentiation (P=0.0192), tumor status (P=0.0108) and pathological stage (P=0.0110). By contrast, no association was observed between islet M2 TAM density and the aforementioned biological and clinical factors. In regards to prognosis, disease-free survival rate was significantly lower in patients with stromal M2 TAM-high tumors (P=0.0270) and in those with alveolar M2 TAM-high tumors (P=0.0283). Furthermore, the overall survival rate was also significantly lower in patients with stromal M2 TAM-high tumors (P=0.0162) and in those with alveolar M2 TAM-high tumors (P=0.0225). Therefore, during NSCLC progression, M2 TAMs may induce tumor cell aggressiveness and proliferation and increase metastatic potential, resulting in a poor prognosis in patients with NSCLC.

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

“…A number of studies demonstrated that M2 macrophage phenotype positively correlates with poor survival and efficient development of metastasis in lung cancer. In order to elucidate the biological and clinical significance of M2 TAMs, a comprehensive clinical study that assessed tissue distribution of CD163+ TAMs in tumor stroma, tumor islets, and alveolar space in 160 NSCLC patients from the Japanese cohort was performed (166). Thus, high stromal and alveolar density of CD163+ TAMs significantly correlated with the C-reactive protein (CRP) level in circulation, the Ki-67 proliferation index and invasive size, tumor differentiation, lymph node metastasis and pathological stage (166).…”

Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing

“…Their analysis revealed that a high level of M1 macrophages in the tumor islets together with a low level of total tumor-infiltrating M2 macrophages were correlated with improved patients’ survival [ 77 ]. Moreover, Sumitomo et al demonstrated that stromal TAMs density in the lungs is associated with lymph node metastasis and reduced overall survival [ 95 ], as well as the density of alveolar macrophages with M2 phenotype (CD163+) was associated with reduced disease free and overall survival. High density of M1 macrophages, characterized by CXCL9, CXCL10, and STAT1 activation, accompanied by the presence of resident memory T cells was also strongly associated with better outcomes in patients with lung cancer [ 96 ].…”

Crosstalk Between Mesenchymal Stromal Cells and Tumor-Associated Macrophages in Gastric Cancer

“…Although the polarized states of macrophages are dictated by cues from the TME, TAMs have been demonstrated to possess an M2-like phenotype prominently in tumor tissues ( 37 , 38 ). In gastric cancer, various studies have presented the critical roles of M2 TAMs in the initiation, progression, and metastasis ( 39 ).…”