Introduction: The diffuse and resistant nature of glioblastoma multiforme (GBM) continues to make therapy for this aggressive intrinsic brain tumor a challenge. As for many attempted novel strategies, immunotherapy approaches for GBM have been thus far largely unsuccessful suggesting unappreciated complexity in glioma biology and immunology. The intra-tumoral heterogeneity of these intrinsic brain tumors results in therapies killing only a subset of the tumor cells; success will require achieving and optimizing an “abscopal effect” where tumor cells not specifically targeted are recognized and attacked as bystanders by the immune system.
Methods: In order to understand the cellular biology of the abscopal effect in-vivo, we have modified an immune-competent, genetically-driven glioma mouse model where a portion of the tumor burden is treated and another untreated portion used as a readout of therapeutic efficacy.
Results: We find that following irradiation of one lesion, anti-PD-L1 therapy enhances the abscopal response (macrophage and T-cells) to the un-irradiated lesion, particularly in gliomas with higher inflammation. Even in gliomas without baseline T-cells, the anti-PD-L1 enhanced abscopal response occurs as an anti-PDL1-driven, macrophage-mediated, and ERK-dependent phagocytosis of tumor cells.
Conclusions: Our results indicate that following radiation and anti-PD-L1 therapy for gliomas, peripherally derived macrophages can be responders in tumors without pre-existing T-cells in the micro-environment.
Patient Care: We have developed a representative genetic mouse model for glioma that mimics the immune micro-environment and systemic immunosuppression found in human patients. Our data indicates that patients with high levels of macrophages and T-cells in the tumor micro-environment could be more susceptible to adjuvant anti-PD-L1 immunotherapy following radiation.
Learning Objectives: By the conclusions of this session, participants should be able to 1) Describe the importance of pre-existing immune infiltration for susceptibility of gliomas to anti-PD-L1 immunotherapy
2)Discuss in small groups potential avenues for boosting the response of gliomas to check-point inhibitors
3)Identify patients, based on histopathologic characteristics of the tumor micro-environment, who may be more susceptible to immune check-point inhibition
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