The Role of Macrophages in Cancers

Dear Colleagues,

A large proportion of tumors consist of non-malignant cells that influence the tumor microenvironment (TME). These include tissue-resident cells and a large proportion of recruited immune cells. In the early stages of tumorigenesis, these immune cells, which include activated T cells and macrophages, are recruited to eradicate the abnormal cells. Macrophages can elicit a robust anti-tumoral response via direct tumor cell elimination, and an adaptive immune response by presenting tumor antigens and secreting cytokines and chemokines that lead to recruitment of cytotoxic CD8+ T cells and natural killer (NK) cells. If eradication is not achieved, the tumor progress and the TME is modified to support the tumor and promote its progression, while the immune system is suppressed. Tumor-associated macrophages (TAM) differentiate and polarize from monocytes or tissue-resident macrophage progenitors recruited from the blood or surrounding tissue. They support tumor progression directly via the release of cytokines and or chemokines. The C-C motif chemokine ligand 2 (CCL2) and the colony-stimulating factor 1 (CSF-1) play an important role in recruitment; interleukins 4/10/13, interferon-gamma (IFN) and the tumor necrosis factor alpha (TNF) for macrophage function and polarization; and vascular endothelial growth factor A (VEGFA) and the angiogenic CXC chemokines CXCL8/12 in the process of vascularization. TAMs can also support the invasion of tumor cells, which detach from the primary tumor, spread through the blood and lymphatic system, and form micro-metastases. For that, TAMs secrete epidermal growth factor ligands and produce cathepsins and matrix metalloproteinases (e.g., MMP9), which improve tumor cell invasive properties. The process of metastasis is closely linked to the WNT signaling pathway, and so the secretion of wingless-related integration site 7b (WNT7B) by TAMs may be a key factor. Under the influence of the TME, the function of the TAMs is altered to support immunosuppression and suppress NK cell and T cell activation and function. For this purpose, they form inhibitory receptors such as the non-classical major histocompatibility complex class I (MHC-I) molecules HLA-E and HLA-G, the immune checkpoint ligands PDL1, PDL2, CD80 (B7-1), and CD86 (B7-2), cytokines IL-10, TGF beta, and C-C motif chemokines CCL 2/3/4/5/20. In addition, TAMs are directly involved in inhibiting T cell cytotoxicity through the expression of arginase 1, which leads to the depletion of L-arginine (essential for re-expression of the T cell receptor). A worthwhile goal should be TAMs in cancer therapy. Promising strategies are being tested as monotherapies or combination therapies with chemotherapy and immunotherapy, where anti-TAM drugs that are targeted towards the processes of recruitment (CCL2, CCR2, CSF1R), survival (CSF1R, caspase 8, bisphosphonates), or reprogramming (CD47, CD40, TLR7, CSF1R) of the macrophages should show their effect. We need more understanding to unravel the negative properties of TAMs in tumorigenesis and tumor progression.

Dr. Pierre Tennstedt
Guest Editor

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• tumor-associated macrophages
• tumor microenvironment
• monocytes
• cancer
• cancer therapy
• bisphosphonates
• cytokines
• chemokines
• immune response
• therapeutic resistance
• immunotherapy