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 part of their immunosurveillance duties, immune cells form part of this microenvironment, and yet cancer cells have devised means to downplay their tumoricidal capabilities.1
Designing drugs that can overcome these immunosuppressive mechanisms and switch the infiltrating immune cells back on poses an attractive therapeutic strategy.
In this context, targeting colony stimulating factor 1 receptor (CSF1R) may offer just such a means of controlling the tumor-associated macrophages (TAMs) that are found in the microenvironment. Several CSF1R inhibitors have been developed that are designed to reprogram macrophages from an immunosuppressive, anti-inflammatory phenotype and kick them back to life in their role as the first line of defense in the antitumor immune response.
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.
A particularly prominent type of tumorinfiltrating immune cell is the macrophage. The cells in this group are responsible for creating the characteristic high level of inflammation in the tumor microenvironment. They are part of the mononuclear phagocyte system, a network of cells that share common properties, including the ability to digest foreign substances and old or damaged cells, and form an important part of the innate immune response.
Macrophages are a very plastic cell type that undergoes changes in phenotype and function in response to cues from their local environment. Although it is widely believed that a continuum of phenotypes likely exists, macrophages switch between 2 main phenotypes: classically activated macrophages (M1) and alternatively activated macrophages (M2). The former are proinflammatory and immunostimulatory, while the latter are anti-inflammatory and immunosuppressive (FIGURE 2).2
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.