Activation and suppression of macrophages: implications for cancer immunotherapy

Abstract

It is widely known that macrophages can be activated to kill tumor cells. It is also known that tumor-infiltrating macrophages can be immunosuppressed. The mechanisms of both tumor killing by activated macrophages and tumor-induced macrophage suppression are not entirely clear. To better understand the mechanisms that macrophages use to kill tumor cells, a murine macrophage cell line, RAW264.7, was fixed with paraformaldehyde, subsequently stimulated with lipopolysaccharide (LPS) and co-cultured with tumor cells. Macrophage activity was assessed by nitric oxide (NO) production and tumor cell growth inhibition in the 3H-thymidine incorporation assay. It was found that fixed macrophages were still able to suppress the proliferation of tumor cells while the production of NO was abrogated. Additionally, a model of tumor-induced suppression of macrophages was developed by co-culturing them with tumor cell conditioned media before adding LPS. Inhibition of macrophage activity by tumor cell products was demonstrated by decreased NO production. This model mimics the suppressed immune system of cancer patients. Next, we will use this model to test substances that aim to reverse immunosuppression of macrophages allowing them to fight tumors.