CCR2 is a CC2-type chemokine receptor, also known as monocyte-attracting protein-1 receptor (MCP-1-R) or CD192. CCR2 is a key functional receptor for CCL2. The CCR2/CCR2 axis directly promotes the survival, growth, invasion, and metastasis of many types of tumors that harbor CCR2.

The structure of CCR2 and its ligand CCL2

CCR2 is a multi-transmembrane protein. Structurally, it adopts the typical folding pattern of a class A GPCR, with seven transmembrane (TM) helices connected by three extracellular (EC) and three intracellular (IC) loops. The extracellular orthosteric pocket of CCR2 can be divided into a major subpocket and a minor subpocket, defined by helices III-VII and helices I-III, VII, respectively. Like other chemokine receptors, CCR2 is predicted to have two conserved disulfide bonds in its extracellular domain: Cys32-Cys277 connecting the N-terminus (NT) to ECL3, and Cys113-Cys190 connecting TM3 to ECL2.

CCL2 is stably anchored in the extracellular half of the receptor transmembrane domain (TMD) and forms extensive interactions with the N-terminus, ECL2, and TM helices (except TM4) of CCR2.

(Data source: Shao Z, et al. Cell Discov. 2022)

Regulation of CCL2/CCR2 signaling pathway

Binding of the CCR2 chemokine receptor leads to the activation of multiple downstream signaling pathways. CCR2-mediated signaling begins with CCL2/CCR2 binding and GPCR activation, followed by activation of the PI3K/Akt pathway, the RAC GTPase pathway, the PKC-dependent pathway, and the JAK/STAT pathway. These pathways exert diverse biological functions, influencing cell survival, proliferation, migration, and differentiation. Downstream activation of the PI3K/Akt pathway protects tumor cells from cell death and promotes proliferation. Activated PI3K induces protein kinase B (Akt) activation through phosphorylation of PDK1 and PDK2 at Thr308 and Ser473, respectively.

(Data source: Fei L, et al. Front Immunol. 2021)

The role of CCL2/CCR2 in physiological processes and cancer-induced inflammation

CCL2 is mainly expressed in endothelial cells, epithelial cells, myeloid cells and smooth muscle cells, fibroblasts, neurons, microglia, endothelial cells, astrocytes and cancer cells, while CCR2 is mainly expressed in monocytes, basophils, T lymphocytes and NK cells.

CCL2 is constitutively expressed in homeostatic functions such as monocyte mobilization and lymphocyte trafficking. However, under pathological conditions, such as chronic inflammation (e.g., cancer), the CCL2 axis promotes the attraction of CCR2-expressing cells, such as TAMs, myeloid cells, Tregs, and cancer cells, as well as cancer cell invasion and extravasation, by increasing the expression of MMPs, endothelial cell hyperpermeability, and angiogenesis. The CCL2/CCR2 axis directly promotes cancer cell survival and dissemination.

(Data source: Pozzi S, et al. Adv Drug Deliv Rev. 2024)

CCL2/CCR2 targeted therapy

Currently, a variety of CCL2/CCR2 axis inhibitors (small molecules and neutralizing antibodies) have been used in clinical trials for cancer and non-malignant diseases.

Neutralization of CCL2 (CNTO888) or CCR2 (MLN1202) in different cancer types with antihuman antibodies has yielded only short-lived and unpredictable anticancer responses. Because inhibition of the CCL2/CCR2 axis can reduce immunosuppression and stimulate infiltration of activated CD8+ T cells, a phase I clinical trial (NCT02723006) targeting CCR2 is currently evaluating the combination of an immune checkpoint inhibitor (ICI) (anti-PD-1 antibody, nivolumab) in patients with advanced melanoma.

Neutralizing antibodies and small molecules targeting CCR2 transiently block CCR2 activity but fail to block CCR2-expressing cells, implying that the target is not permanently lost or depleted. This important consideration, given potential clinical translation strategies, suggests that the CCL2/CCR2 axis is a valuable player and could be a target for delivery systems. Currently, no delivery system for these therapies has been tested in clinical trials to enhance their efficacy. This paves the way for research and development to translate into industry and the clinic.

(Data source: Pozzi S, et al. Adv Drug Deliv Rev. 2024)