Macrophage polarization in the tumor following radiation therapy is mediated by NFκB p50 (66.30)

Abstract

Abstract By causing the death of cancer cells, radiation therapy has been proposed to provide both tumor antigen and endogenous immune adjuvants to initiate de novo tumor-specific immune responses. However, our experiments have shown that following radiation therapy of tumors in mice there is a rapid influx of tumor macrophages that polarize towards immune suppression. In this study we investigate the mechanisms by which newly recruited macrophages are polarized following exposure to irradiated cancer cells. Macrophage exposure to irradiated cancer cells causes a switch from TNFα to IL-10 secretion following LPS stimulation. Using luciferase reporter assays we identify that this is a transcriptional switch consistent with the action of NFκB p50 homodimers. Using macrophages from knockout mice we confirm that the immune suppressive polarization of macrophages following exposure to irradiated cancer cells requires NFκB p50. To identify the source of the upstream signal causing macrophage polarization, we determined that combined blockade of the TGFβ receptor and the Mer receptor for Gas6 bound to exposed phosphatidylserine was able to restore TNFα secretion on LPS stimulation. We propose that wound repair following radiation therapy limits control of residual disease by increasing immune suppression in the tumor. Directing the polarization of newly recruited tumor macrophages following radiation therapy represents a strategy to enhance adaptive immune control of residual cancer cells.