IMMU-24. TEMOZOLOMIDE INDUCED IMMUNE DYSFUNCTION REQUIRES THE PRESENCE OF INTRACRANIAL TUMORS

Abstract

Abstract Temozolomide was recently shown to cause peripheral and intra-tumoral T cell dysfunction in a dosing schedule dependent fashion. Standard dose (SD) temozolomide (TMZ) resulted in T cell dysfunction precluding response to immune checkpoint inhibition that was avoided with a metronomic dosing (MD) schedule. Building on these studies, we investigated the TMZ-induced immune changes in tumor and non-tumor bearing models to understand the interaction of an intracranial tumor on host immunity. C57BL/6 mice underwent intracranial implantation of GL-261 tumor cells. Tumor bearing animals and naïve animals with no tumor were treated with standard dose (50 mg/kg x 5 days) or metronomic dose (25mg/kg x 10 days) of TMZ. Peripheral blood and spleens were collected for flow cytometry, ELISA and luciferase killing assay. Tumor bearing animals treated with SD TMZ demonstrated an increase in circulating myeloid derived suppressor cells (MDSCs), an upregulation of exhaustion markers on endogenous host CD8 T cells (TIM3, LAG3) and a decrease in IFN-gamma secretion from adoptively transferred T cells (tested via ELISA). The cell killing capability of adoptively transferred T cells was not reduced after exposure to a TMZ treated host. Non-tumor bearing animals treated with SD TMZ did not demonstrate an increase in circulating MDSCs or exhaustion markers on endogenous T cells. IFN-gamma secretion from adoptively transferred T cells was still reduced in these animals. The host immune dysfunction induced by TMZ is dependent on the presence of an intracranial malignancy. The mechanisms causing these changes are under active investigation.