Modifying tumor associated macrophage function through cannabinoid receptor 2

In human breast cancers, tumor infiltration by tumor associated macrophages (TAMs) correlates with multiple markers of poor prognosis: higher tumor macrophage counts are associated with higher tumor grade, higher tumor vascular density, and reduced overall survival [1]. TAMs secrete biologically active molecules that promote tumor growth and metastasis[1]. Additionally, unique subpopulations of TAMs contribute to the immunosuppressive microenvironment that significantly enhances tumor genesis by limiting vital anti-tumor immune responses [2], however the mechanisms that regulate TAM development and their actions within the tumor microenvironment remain poorly understood. Pre-clinical studies demonstrate that macrophage ablation retards tumor progression[3], suggesting that TAMs may be a viable target for eliciting an anti-tumor response. We have therefore begun to analyze the effects of novel cannabinoid agonists on TAMs in a murine model of breast cancer. Macrophage expression of cannabinoid receptor 2 (CB2) is induced by inflammatory stimuli and regulates multiple functions including chemotaxis and antigen presentation[4]. Recent findings in our lab and by others indicate that CB2 agonists significantly reduce tumor burden and metastasis in several models. Although the in vivo anti-tumor efficacy of cannabinoids is mimicked in continuously cultured cancer cells in vitro, cannabinoid potency for direct elicitation of apoptosis in cancer cells is far lower, indicating that other mechanisms (perhaps other cell types within the tumor) are involved in vivo. We have recently obtained evidence that: 1) CB2 agonists mediate inhibition of primary tumor growth and metastasis in vivo, 2) significant infiltration of TAMs occurs within the developing tumor in this murine model, 3) administration of a CB2 agonist increases populations of pro-inflammatory M1 macrophages (MHC Class II-high, iNOS high) in both the primary tumor and in the spleen of tumor bearing mice, and 4) a concurrent increase in the proportion of CD8+ cytotoxic T lymphocytes is also observed within the primary tumor upon CB2 agonist treatment.