Tmic-12. tmz results in priming of host immunity and changes in gbm tumor pdl-1 expression in a dose dependent fashion that can be leveraged for combination with immune checkpoint blockade

In this study, we hypothesised that dose modified TMZ improves GBM response to immune check point blockade by priming host immunity and changing tumor microenvironment. Murine glioma cell lines were treated with TMZ and checked for PD-1, PDL-1. mice were injected with different doses of TMZ to evaluate PD-1, PDL-1 in lymphocytes at different time points post TMZ. mice recieved OT- 1 splenocytes pre and post TMZ to determine effects of TMZ on antigen specific T cell recovery. GL-261 and GL-261 overexpressing MGMT (GL-MGMT) were implanted intracerebrally to mice and treated with PD-1 blockade and TMZ for survival study. PDL-1 was increased in murine glioma cells with TMZ in a dose dependent fashion. Although TMZ induced lymphopenia, this was associated with an increase in PD-1 and decrease in TIM3 in lymphocytes at 1 week post treatment indicative of T cell activation. Antigen specific T cells (OT-1) expanded more in the setting of TMZ treatment and peaked at 2 weeks post-treatment. GL-261 and GL-MGMT tumor bearing animals treated with PD-1 blockade showed moderate extension in survival. GL-MGMT tumors did not respond to TMZ, whereas GL-261 tumors treated with TMZ survived longer. GL-261 tumors treated with combination of PD-1 blockade and TMZ showed extended survival. However, GL-MGMT tumors had reduced survival when TMZ was combined with PD-1 inhibition. TMZ induced higher expression of PD-1 in T cells and PDL-1 in GBM tumor cells. Antigen specific T cells expand in the ...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MICROENVIRONMENT Source Type: research