The tumor microenvironment (TME) comprises a diverse array of immune cells recruited into the supportive niche that surrounds the tumor through interactions between chemokines and their cell surface receptors. Chemokine receptor type 2 (CCR2), a major recruiter of circulating monocytes that subsequently develop into a protumoral type of macrophage within the TME, has emerged as a promising therapeutic target.
Efforts to bring CCR2 antagonists to the clinic have been abandoned by several pharmaceutical companies in recent years, but a more nuanced understanding of the role of the chemokine network in the initiation and progression of tumors is fostering development of several drugs, including a dual CCR2/chemokine receptor type 5 (CCR5) antagonist.
The CCR2 signaling axis may also offer a way to overcome challenges for an established therapeutic strategy. Chimeric antigen receptor (CAR) T cells genetically engineered to express CCR2 could penetrate more readily into the TME, which has been a barrier to the antitumor efficacy of CAR T cells in solid tumors until now.
Masters of Migration
The cells of the immune system secrete a range of chemical messengers known as cytokines that facilitate communication with one another and the host. Chemokines are a subfamily of cytokines that specialize in mediating migration; they function as chemoattractants, providing directional cues for immune cells to recruit them to sites of inflammation where immune cells are needed for tissue defense and repair.
Figure. Chemokines in Action
There are several subgroups of chemokines, defined by the position of conserved cysteine amino acids within their structure; in the CC chemokines, there are 2 adjacent cysteines near the beginning of the protein.
Homeostatic chemokines, which maintain the status quo in many tissues, are expressed continuously. In the event of infection, injury, or tissue damage, inflammatory chemokines can also be expressed that help to address the problem.
Chemokines exert their effects by binding to transmembrane, G protein–coupled chemokine receptors on the surface of target cells. Responding cells migrate along a chemokine gradient toward areas with high local concentrations.1-3
CCR2 functions predominantly as a receptor for chemokine ligand 2 (CCL2), an inflammatory CC chemokine, also known as monocyte chemoattractant protein-1, reflecting its major role in the regulation of monocyte migration to sites of pathologic inflammation.
Alternative splicing of the gene produces 2 isoforms, 2A and 2B, that are expressed in different tissues by different cells and can induce varied biological responses. The majority of CCR2 is expressed by monocytes and natural killer cells, although it is also found on other cell types.
Induced by a range of stimuli, including platelet- derived growth factor, CCL2 is expressed by different cell types, including endothelial cells, fibroblasts, and smooth muscle cells. Monocytes are also major producers of CCL2, establishing a positive feedback loop to recruit more monocytes to the site of inflammation (Figure
Monocytes are components of the mononuclear phagocyte system, a class of specialized cells that occur throughout the body and share a phagocytic function, primarily in the orchestration of the innate immune response. They are produced in the bone marrow from hematopoietic stem cells, then enter the blood stream and the spleen. They patrol the body and penetrate the tissues, ready to be mobilized in response to injury or inflammation.
The many intricacies of monocyte function in the immune system are still being teased apart—both inflammatory and no-inflammatory monocytes have been described—but their best understood and their likely primary function is to serve as the precursors for 2 other types of white blood cells: macrophages and dendritic cells (DCs). As monocytes enter the tissue, they differentiate into subtypes of macrophages and DCs, with a range of functions, depending upon local environmental cues.
Macrophages, for example, have a phenotypic continuum, from the classically activated, proinflammatory, proimmunity M1 type to the alternatively activated, anti-inflammatory, immunosuppressive M2 type at the 2 extremes. The latter are required at the later stages of the inflammatory response to limit damage to normal cells and allow time for healing and remodeling.9
A Cancer Hallmark
Tumors don’t exist in isolation; they are surrounded by host cells and tissues, with which they can interact. Tumor cells can use those interactions to manipulate their local microenvironment, creating a supportive niche. The TME fundamentally influences tumor biology and acts as a barrier to effective anticancer therapy.
A defining feature of the TME is the infiltration of immune cells, which enter the stroma in their capacity as immunosurveillers for the antitumor immune response. Monocytes and macrophages have been universally observed across tumor types, although to varying degrees. In some tumors, they constitute the majority, while in others they are less prevalent.10