A growing appreciation of the role of the tumor microenvironment in fostering the development of malignancies is prompting the pursuit of anticancer therapies that target components of this supportive niche as opposed to the tumor itself.
As a class, CSF1R inhibitors have proved mostly disappointing in early clinical trials when used as monotherapy. Researchers believe their true potential can be tapped by combining them with other anticancer drugs, such as immune checkpoint inhibitors. Combinations are being explored in several early-stage clinical trials.
Macrophages in Microenvironment
Tumors do not grow in isolation. They are surrounded by a network of normal cells, tissues, and vasculature that are collectively dubbed the tumor microenvironment. In recent years, it has become increasingly evident that the microenvironment is not merely a bystander in tumor development and progression, that it can be corrupted by the tumor to become an active collaborator (FIGURE 1).1
Figure 1. Cancer Hallmarks in the Microenvironment1
Among the components that make up the tumor microenvironment are many types of immune cells. These cells are part of the antitumor immune response and can help to control tumor growth. However, tumors have developed mechanisms of immunosuppression that blunt the immune cells’ activity and foster tumor growth.
Figure 2. Factors Affecting Immune Response
Tumors capitalize on this phenotypic switch by secreting cytokines into the tumor microenvironment that foster the development of M2-like TAMs that promote tumor growth by providing growth factors and proangiogenic molecules and suppressing the antitumor immune response.1,3,4
Central Role of CSF1R
The cells that make up the mononuclear phagocyte system are governed by a number of signaling pathways that translate external environmental cues into cellular activity. Particularly crucial, especially in macrophages, is CSF1R-mediated signaling.
CSF1R is a tyrosine kinase receptor that spans the cell membrane and is activated by the binding of 2 known cytokine ligands: colony stimulating factor 1 (CSF1) and IL-34. Upon ligand binding, 2 receptor molecules pair up and several key tyrosine residues on the part of the receptor that protrudes into the cell are phosphorylated. This acts as a binding platform for downstream-signaling molecules and activates several signaling cascades, including the PI3K/AKT, mitogen-activated protein kinase, and SRC pathways.
These pathways ultimately sustain the growth, proliferation, survival, differentiation, and function of macrophages and other myeloid cells, including myeloid-derived suppressor cells, although much less is understood about the contribution of the signaling networks to the function of these other cell types.
The CSF1R pathway also may play an important role in macrophage polarization; that is, the M1/M2 dichotomy, which has important implications for the development of a variety of pathological conditions.
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