CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

Abstract

Macrophages abundantly found in the tumor microenvironment enhance malignancy1. At metastatic sites a distinct population of metastasis associated macrophages (MAMs) promote tumor cell extravasation, seeding and persistent growth2. Our study has defined the origin of these macrophages by showing Gr1+ inflammatory monocytes (IMs) are preferentially recruited to pulmonary metastases but not primary mammary tumors, a process also found for human IMs in pulmonary metastases of human breast cancer cells. The recruitment of these CCR2 (receptor for chemokine CCL2) expressing IMs and subsequently MAMs and their interaction with metastasizing tumor cells is dependent on tumor and stromal synthesized CCL2 (FigS1). Inhibition of CCL2/CCR2 signaling using anti-CCL2 antibodies blocks IM recruitment and inhibits metastasis in vivo and prolongs the survival of tumor-bearing mice. Depletion of tumor cell-derived CCL2 also inhibits metastatic seeding. IMs promote tumor cell extravasation in a process that requires monocyte-derived VEGF. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer (Fig S2)3-6. Our data provides the mechanistic link between these two clinical associations and indicates new therapeutic targets for treating metastatic breast disease.

From sentinel cells to inflammatory culprits: cancer‐associated fibroblasts in tumour‐related inflammation

“…Similarly, prostate fibroblasts in benign prostatic hyperplasia secrete cytokines and chemokines that support an inflammatory proliferative microenvironment [52]. At more advanced tumourigenic stages, CAFs facilitate trafficking of myeloid cells into metastasizing tumours: in a mammary carcinoma model of pulmonary metastasis, stromal-derived CCL2 recruits CD11b + Gr1 + Ly6c + inflammatory monocytes that support pulmonary metastasis [69].…”

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

“…CCL2) have been known to be associated with macrophage infiltration in experimental and human tumors for over 25 years (e.g. [12][13][14][15][16]). For instance, gliomas are characterized by the long recognized production of a wide spectrum of chemokines, by the expression of chemokine receptors and by the correlations between chemokine production/receptor expression and clinical outcome; the chemokine repertoire of gliomas includes CCL2, CXCL8, CXCL12, CXCL10, CCL3L1, CX3CL1 (e.g.…”

“…Strategies include interference with the M-CSF axis [13] or chemokine expression/function (in particular CCL2, e.g. [13,15]), or depletion of angiogenic monocyte subsets [48,49].…”

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

“…14 This model has been instrumental for studying tumor-host interactions and anti-tumor immune responses. 15–18 The MMTV-PyMT model has been used to test CTLA-4 or PD-1 checkpoint inhibition in combination with other therapeutic approaches such as irradiation or inhibition of the tyrosine kinase Axl. 19–21 In these studies, combination approaches provided clinical benefit, whereas single-treatment with checkpoint inhibitors was not efficacious.…”