The CCR2/MCP-1 Chemokine Pathway and Lung Adenocarcinoma

Abstract

Host anti-tumor immunity can be hindered by various mechanisms present within the tumor microenvironment, including the actions of myeloid-derived suppressor cells (MDSCs). We investigated the role of the CCR2/MCP-1 pathway in MDSC-associated tumor progression in murine lung cancer models. Phenotypic profiling revealed maximal expression of CCR2 by tumor-resident MDSCs, and MCP-1 by transplanted TC1 tumor cells, respectively. Use of CCR2-knockout (CCR2-KO) mice showed dependence of tumor growth on CCR2 signaling. Tumors in CCR2-KO mice had fewer CCR2low MDSCs, CD4 T cells and Tregs than WT mice, and increased infiltration by CD8 T cells producing IFN-γ and granzyme-B. Effects were MDSC specific, since WT and CCR2-KO conventional T (Tcon) cells had comparable proliferation and production of inflammatory cytokines, and suppressive functions of WT and CCR2-KO Foxp3+ Treg cells were also similar. We used a thioglycolate-induced peritonitis model to demonstrate a role for CCR2/MCP-1 in trafficking of CCR2+ cells to an inflammatory site, and showed the ability of a CCR2 antagonist to inhibit such trafficking. Use of this CCR2 antagonist promoted anti-tumor immunity and limited tumor growth. In summary, tumor cells are the prime source of MCP-1 that promotes MDSC recruitment, and our genetic and pharmacologic data demonstrate that CCR2 targeting may be an important component of cancer immunotherapy.

The Role of Macrophages in Cancer Development and Therapy

“…To break the CCL2-CCR2 interaction and inhibit monocyte recruitment to the TME, both CCR2 and CCL2 antagonists are used ( Figure 3 ). Many preclinical studies showed high efficacy of CCL2/CCR2 antagonists, e.g., in the mouse model of lung adenocarcinoma, targeting CCR2 with a small molecule inhibitor not only reduced recruitment of M2-type macrophages but also induced tumor infiltration of activated CD8 + T cells [ 116 ]. Administration of CCL2 neutralizing antibodies reduced tumor growth, inhibited angiogenesis, and macrophage infiltration in a mouse model of clear cell renal cell carcinoma [ 117 ].…”

MCP‑1 targeting: Shutting off an engine for tumor development (Review)

“…MCP-1 acts as an engine that drives tumor progression and therefore may serve as an effective therapeutic target. In this regard, the CCR2 blockade (i.e., the MCP-1 receptor) shows promise due to the antitumor effects it exerts (29,36,66,75). However, MCP-1 is secreted not only by tumor cells, but also by stromal cells surrounding the tumor parenchyma (81).…”

“…MCP-1 also recruits Treg lymphocytes into the TME via the downregulation of TNFSF15, whereby TNFSF15 levels are inversely correlated with the degree of CD4 + CD25 + FOXP3 + Treg lymphocyte infiltration (58). In this regard, there is a reduction of CD4 + FOXP3 + Treg lymphocytes and induction of CD8 + T-lymphocyte cytotoxicity, which restricts tumor growth in a CCR2 knockout mouse lung adenocarcinoma model (75). Similarly, blocking of the MCP-1/CCR4 signaling pathway using a CCR4 antagonist inhibits tumor growth and prolongs survival time in patients with head and neck squamous cell carcinoma (HNSCC) (76).…”

PET Imaging Radiotracers of Chemokine Receptors

“…In addition, studies using CCR2-deficient mice models indicated that the receptors were involved in the development of Alzheimer’s-like pathology and obesity [ 13 ]. Furthermore, changes in CCR2 expression were noted in cardiac and pulmonary disorder models and, to some extent, in cancer models such as adenocarcinoma [ 84 , 85 ]. Blockade of CCR2 was demonstrated to be viable in treating various inflammatory diseases, experimentally and clinically [ 86 , 87 ].…”