Macrophages in Gastric Cancer

Gastric cancer (GC) is a globally important disease. With over 1 million estimated new cases annually, GC is the fifth most diagnosed malignancy worldwide. Due to its frequently advanced stage at diagnosis, mortality from GC is high, making it the third most common reason for cancer-related deaths. When diagnosed in an advanced stage, GC is characterized by a very poor prognosis, with a five-year overall survival rate of about 5%. GC is a heterogeneous disease and several subtypes have been described anatomically, histologically, and genetically. Historically GC has been classified into two main subgroups, intestinal and diffuse, according to different microscopic features. Moreover, chronic inflammation and H. pylori infection are the classical determinants in GC development.

The Interplay Between Macrophages and GC

In the GC microenvironment, cross-talk between tumor-associated macrophages (TAMs) and tumor cells has been shown to extremely conduce to the progression of GC. Tumor cells can secrete a few cytokines and growth factors that mediate the M2 polarization of macrophages, such as prostaglandin E2 (PGE2), interleukin-6 (IL-6), and colony-stimulating factor-1 (CSF-1). M2 TAMs can secret epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), hyperglycemic factor (HGF), and vascular endothelial growth factor (VEGF) to stimulate the progression of tumors. In gastritis and gastric cancers, marked infiltrating macrophages are recruited by epithelium-derived chemokines and cytokines, leading to secretion of a few pro-inflammatory cytokines like tumor necrosis factor (TNFα) and stimulation of tumor growth. Activated macrophages are reported to produce nitric oxide synthase (NOS) and/or reactive oxygen species (ROS) that lead to epigenetic changes in the gastric epithelial cells. M2 TAMs can be reprogrammed into M1 TAMs by interfering with the interactive signals, resulting in a shift in the immune microenvironment.

Fig.1 The interplay between TAMs and gastric cancer. (Oya, 2020)

Clinical Implications of TAMs in GC

One characteristic of the tumor microenvironment (TME) in GC is chronic inflammation derived from infection, such as H. pylori. The function of macrophages is important in chronic inflammation and H. pylori infection of gastric. H. pylori and other pathogens impair M1 TAMs responses inducing an M2-like state, and increase the rate of ROS-induced macrophage apoptosis, enhancing the risk of disease progression. The presence and density of TAMs have been correlated with prognosis and resistance to therapy. Some studies reveal that the number of infiltrating M2 TAMs and total TAMs could be poor prognostic elements for GC patients, while infiltrating M1 TAMs may be connected with an advantageous survival rate. The immunosuppressive and pro-angiogenic phenotype that TAMs promote could be of primary interest especially in diffuse GC and in the genomically stable subgroup, where the presence of M2 TAMs was found to be higher and could contribute to an immunosuppressive phenotype.

Therapies of Targeting TAMs in GC

TAMs emerge to have multiple functions in GC, including tumorigenesis, immune evasion, metastasis, and chemoresistance. The potential function of macrophages in tumor development has driven the development of new anti-cancer treatments, such as 1) reprogramming M2 TAMs into M1 TAMs by disrupting NFkB signaling or interacting with TNF-α; 2) inhibiting TAMs from recruiting to the tumor site by targeting the chemokine ligand 2-chemokine receptor 2 (CCL2-CCR2) axis; 3) depleting TAMs and inhibiting intratumoral macrophage M2 polarization by targeting CSF-1/CSF-1 receptor, endostatin or bisphosphonates. Despite the attractive role of TAMs and their implication in the immune response, their role and therapeutic implication need to be further validated.

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Reference

1. Oya, Y.; et al. Tumor microenvironment in gastric cancers. Cancer Sci. 2020, 111(8):2696-2707.