Increased infiltration of TAMs into NSCLC correlates with a poor prognosis [5, 9]. However, the mechanisms for this effect remain unclear. TAM derived molecules that function to suppress immune activation, promote extracellular matrix (ECM) remodeling may play important roles in NSCLC progression.
In the present study, the rational we selected IL-10, cathepsin B or cathepsin S, is that they were reported to be closely associated with TAMs in recent literatures [10–12, 24]. IL-10 is widely known as an potent immunosuppressive cytokine associated with cancer [13, 25]. It is produced by a number of cells, including tumor cells and TAMs[14, 25]. Cathepsins B, cathepsin S, proteolytic enzymes, were thought to facilitate the breakdown of basement membranes thereby promoting cancer cell invasion into surrounding normal tissues. TAM expressed cathepsin B or cathepsin S in pancreatic islet, breast or prostate cancer animal models. In our study, we showed, TAM expressed high levels of IL-10, cathepsin B, but not cathepsin S in NSCLC.
Our study suggested that increased IL-10 expression of TAM in NSCLC patients correlated with late stage disease (stage II, III and IV), lymph node metastases, pleural invasion, lymphovascular invasion and poor differentiation. Although recent animal model studies indicated that cathepsin B or cathepsin S expressed by TAM play an important role in tumor progression[10, 11], and we also found cathepsin B upregulated in TAM, we failed to demonstrate any correlation between cathepsin B in TAM and stage, lymph nodal metastasis, pleural invasion or differentiation in NSCLC.
TAMs are derived from blood monocytes that are attracted to a tumor by cytokines and chemokines. In the tumor microenvironment, monocytes differentiate into a distinct macrophage phenotype, which is characterized by the production of high level of IL-10. TAM with high IL-10 expression level may tune inflammatory responses and adaptive Th2 immunity, exhibit anti-inflammatory and tissue remodeling functions and thereby, to favor tumor progression. We demonstrated that NSCLC patients with late stage disease had a higher level of IL-10 expression in TAM, which further supports this hypothesis.
IL-10 is a potent immunosuppressive factor that may promote lung cancer growth by suppressing macrophage function and enabling tumors to evade immunosurveillance. The potential importance of IL-10 in cancer progression is supported by reports of an association between high IL-10 levels in serum or in tumors and worse survival in lung cancer patients. However, other authors demonstrated that lack of IL-10 expression by the tumor was associated with a worse survival in patients with stage I NSCLC . The reason for these conflicting results might be that, both tumor cells and stromal(including macrophage) cells can secrete IL-10. Additionally, Wagner S et al identified that macrophage was the major source of IL-10 in gliomas. So it is important to isolate TAM from tumor cells to study the role of IL-10 in the progression of cancer. In our study, we demonstrated the phenotype of isolated TAM was closely associated with clinicopathological features. We can predict tumor size, lymph nodal metastasis and pleural invasion through.IL-10 expression in isolated TAM. We also found that the high expression of IL-10 in TAM was associated with poorly differentiation, which highlighted a significance role of IL-10 secreted by TAM in tumor aggressiveness.
A crucial step of cancer invasion and metastasis is the destruction of basement membrane by proteases. Recent studies showed invasion of cancer cell is increased by the proteases secreted from TAMs. Cathepsin B or cathepsin S has been implicated in the progression of various human cancers, including bladder, breast, prostate and lung cancers [17, 28–30]. The cellular source of this protease in human cancers, consisting of both tumor cells and stromal cells (e.g., fibroblasts, endothelial cells, and TAMs), has remained elusive. Studies using animal models have demonstrated that TAMs are the primary source of high levels of cathepsin B or cathepsin S in prostate, pancreatic islet cancers, and mammary tumors, and its expression by TAMs plays critical roles in multiple stages of tumor growth and metastasis[10, 12, 29]. Our studies demonstrated that TAM isolated from NSCLC overexpressed cathepsin B but not cathepsin S, and the cathepsin B levels were not associated with NSCLC stage, lymph metastasis, lymphovascular invasion or histological differentiation.