Therapeutic radiation drives leptomeningeal dissemination of medulloblastoma through an innate immune process.

Abstract

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives medulloblastoma leptomeningeal dissemination, whereas premedication with corticosteroids prevents both inflammation and the pro-metastatic effect of radiation. In murine model systems, inflammation in the tumor microenvironment secondary to external beam radiation is both sufficient and necessary to drive leptomeningeal metastases.