Abstract
Using genetic interventions, we previously determined that C-C motif chemokine ligand 2 (CCL2) promotes malignant pleural effusion (MPE) formation in mice. Here we conducted preclinical studies aimed at assessing the specific therapeutic potential of antibody-mediated CCL2 blockade against MPE. For this, murine MPEs or skin tumors were generated in C57BL/6 mice by intrapleural or subcutaneous delivery of lung (LLC) or colon (MC38) adenocarcinoma cells. Human lung adenocarcinoma cells (A549) were used to induce MPEs in severe combined immunodeficient mice. Intraperitoneal antibodies neutralizing mouse CCL2 and/or CCL12, a murine CCL2 ortholog, were administered at 10 or 50 mg/kg every three days. We found that high doses of CCL2/12 neutralizing antibody treatment (50 mg/kg) were required to limit MPE formation by LLC cells. CCL2 and CCL12 blockade were equally potent inhibitors of MPE development by LLC cells. Combined CCL2 and CCL12 neutralization was also effective against MC38-induced MPE and prolonged the survival of mice in both syngeneic models. Mouse-specific CCL2-blockade limited A549-caused xenogeneic MPE, indicating that host-derived CCL2 also contributes to MPE precipitation in mice. The impact of CCL2/12 antagonism was associated with inhibition of immune and vascular MPE-related phenomena, such as inflammation, new blood vessel assembly and plasma extravasation into the pleural space. We conclude that CCL2 and CCL12 blockade are effective against experimental MPE induced by murine and human adenocarcinoma in mice. These results suggest that CCL2-targeted therapies may hold promise for future use against human MPE.
Highlights
Malignant pleural effusion (MPE) is a frequent and clinically significant systemic manifestation of various tumors that adversely affects patient survival and quality of life [1], [2]
We have identified a predominant mononuclear/macrophage cellular infiltrate in experimental and human MPE, and have shown that these cells are recruited to the malignancy-affected pleura by tumor-derived C-C chemokine ligand 2 (CCL2) [11], [17], [18]
To investigate the potential impact of CCL2 and/or CCL12 neutralization on MPE, C57BL/6 mice received intrapleural Lewis lung carcinoma (LLC) cells followed by intraperitoneal control or antibody treatments at 10 mg/kg (Figure 1C)
Summary
Malignant pleural effusion (MPE) is a frequent and clinically significant systemic manifestation of various tumors that adversely affects patient survival and quality of life [1], [2]. We have shown that targeted disruption of biologic pathways that mediate inflammation, angiogenesis, and vascular hyperpermeability during MPE development can yield meaningful improvements in effusion control and survival [13], [14], [15], [16]. Along these lines, we have identified a predominant mononuclear/macrophage cellular infiltrate in experimental and human MPE, and have shown that these cells are recruited to the malignancy-affected pleura by tumor-derived C-C chemokine ligand 2 (CCL2) [11], [17], [18]. This work identified CCL2 as a promising therapeutic target in preclinical MPE, attempts at suppressing CCL2 signaling using clinically relevant methods have not been undertaken
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