Macrophage and Cancer Cell Crosstalk via CCR2 and CX3CR1 is a Fundamental Mechanism Driving Lung Cancer

Rationale: Recent studies indicate that tumor associated macrophages with an M2 phenotype can influence cancer progression and metastasis, but the regulatory pathways remain poorly characterized.

Objectives: This study investigated the role of tumor-associated macrophages (MΦ) in lung cancer.

Methods and results: Co-culturing of MΦ with mouse Lewis Lung Carcinoma (LLC1) and 10 different human lung cancer cell lines (adenocarcinoma, squamous and large cell carcinoma) caused upregulation of CCR2/CCL2 and CX3CR1/CX3CL1 in both the cancer cells and the MΦ. In the MΦ-tumor cell system, IL-10 drove CCR2 and CX3CR1 upregulation, while CCL1, G-CSF and MIP1a were required for the upregulation of CCL2 and CX3CL1. Downstream phenotypic effects included enhanced LLC1 proliferation and migration and MΦ M2 polarization. In vivo, MΦ depletion (clodronate, MaFIA mice) and genetic ablation of CCR2 and CX3CR1 all inhibited LLC1 tumor growth and metastasis, shifted tumor-associated MΦ towards M1 polarization, suppressed tumor vessel growth and enhanced survival (metastasis model). Furthermore, mice treated with CCR2 antagonist mimicked genetic ablation of CCR2 by reducing tumor growth and metastasis. In human lung cancer samples, tumor MΦ infiltration and CCR2 expression correlated with tumor stage and metastasis.

Conclusions: Tumor-associated MΦ play a central role in lung cancer growth and metastasis, with bidirectional crosstalk between MΦ and cancer cells via CCR2- and CX3CR1-signaling as an central underlying mechanism. These findings suggest that the therapeutic strategy of blocking CCR2 and CX3CR1 may prove beneficial for halting lung cancer progression.