The Angiotensin Receptor Blocker Losartan Suppresses Growth of Pulmonary Metastases via AT1R-Independent Inhibition of CCR2 Signaling and Monocyte Recruitment

Abstract

Inflammatory monocytes have been shown to play key roles in cancer metastasis through promotion of tumor cell extravasation, growth, and angiogenesis. Monocyte recruitment to metastases is mediated primarily via the CCL2-CCR2 chemotactic axis. Thus, disruption of this axis represents an attractive therapeutic target for the treatment of metastatic disease. Losartan, a type I angiotensin II receptor (AT1R) antagonist, has been previously shown to have immunomodulatory actions involving monocyte and macrophage activity. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, we investigated the effects of losartan and its primary metabolite on CCL2-mediated monocyte recruitment and CCR2 receptor function using mouse tumor models and in vitro human monocyte cultures. We show, in this study, that losartan and its metabolite potently inhibit monocyte recruitment through the noncompetitive inhibition of CCL2-induced ERK1/2 activation, independent of AT1R activity. Studies in experimental metastasis models demonstrated that losartan treatment significantly reduced the metastatic burden in mice, an effect associated with a significant decrease in CD11b + /Ly6C +-recruited monocytes in the lungs. Collectively, these results indicate that losartan can exert antimetastatic activity by inhibiting CCR2 signaling and suppressing monocyte recruitment and therefore suggest that losartan (and potentially other AT1R blocker drugs) could be repurposed for use in cancer immunotherapy.

Combining microenvironment normalization strategies to improve cancer immunotherapy

“…In particular, TGF-β, which is a target molecule of stroma normalization, can affect immunotherapy through many mechanisms, such as the intratumoral distribution of T cells (18,65). Indeed, stroma-normalizing mechanotherapeutic drugs might have the capacity to directly act on immune and endothelial cells (66)(67)(68). Another process not included in the model is the delivery of ICB antibodies from the bloodstream into the tumor; instead, we model their activity, the lack of dependence of T-cell infiltration from VEGF levels, and the repulsion of T cells from cancer cells via CXCR4 signaling, and we assume that migration rates of T cells do not depend on oxygen levels.…”

Candesartan could ameliorate the COVID-19 cytokine storm

“…CXCL16 is involved in Angiotensin II associated metabolic disorders and atherosclerosis, and its secretion is blocked by ARBs [ 121 , 122 ]. ARB treatment reduces MCP-1 upregulation during lung injury, inhibits monocyte recruitment and reduces lung fibrosis development [ 123 , 124 ]. ARBs downregulate the proinflammatory chemokines CCL4 , CCL7 and CXCL10 [ [125] , [126] , [127] , [128] ].…”

“…Reported molecular mechanisms of ARBs protective effects in lung function include reduction of MCP-1 upregulation, CCR2 signaling, monocyte recruitment and lung fibrosis [ 123 , 124 ], downregulation of pro-inflammatory chemokines CCL4, CCL7 and CXCL10, and autoimmune inflammation [ 125 , 126 ], attenuation of sepsis-induced acute lung injury, TNF-alpha, IL-6, IL-1beta, NF-kappaB, degradation of IkappaB-alpha, inhibition of p38MAPK phosphorylation, extracellular signal-regulated kinase ½,and c-Jun N-terminal kinase, critical for cytokine release as well as protecting from ALI/ARDS [ 171 ]. The direct efficacy of ARB treatment in coronavirus infections has been demonstrated by their reduction of lung injury and pulmonary edema in a SARS-CoV infection mouse model and after SARS-CoV spike protein injection in mice, a clinically relevant post-infection model [ 9 ].…”

A Role for Dogs in Advancing Cancer Immunotherapy Research

“…Given that there are no currently approved (or affordable) pure CCR2 antagonists available for evaluation in dogs, our group has identified several drugs, most notably angiotensin receptor antagonists (ARBs), that can be repurposed as monocyte migration inhibitors. For example, we reported recently that the ARB losartan exerts potent antitumor activity by blocking signaling via the CCR2 chemokine receptor, thereby inhibiting the recruitment of inflammatory monocytes into tumor tissues, leading to overall tumor macrophage depletion (62). A recently completed clinical trial in dogs with metastatic osteosarcoma treated with high-dose losartan immunotherapy demonstrated significant antitumor activity and systemic suppression of monocyte migration (Regan et al, in review).…”