Leveraging Innate Immune Sensors to Generate Durable Anti-Glioma Adaptive Immune Responses

<p>Glioblastoma is an aggressive primary brain malignancy harboring a tumor microenvironment that is mostly devoid of T cell effector infiltration but is dominated by immune suppressive microglia, macrophages, and myeloid-derived suppresser cells. These innate immune cells display impaired phagocytosis and antigen presentation and are inadequate for triggering the subsequent immune activating signals needed for anti-tumor adaptive effector responses. Glioblastoma tumors can further restrict phagocytosis and subsequent tumor antigen presentation by the upregulation of the antiphagocytic “don’t eat me” ligand CD47. Here we tested whether activation of multiple conserved innate immune pathways could initiate proinflammatory conversion of suppressive myeloid populations, activation of antigen presenting cells, and priming of anti-glioma adaptive immune responses. We show in multiple murine tumor models reflecting the immune suppressive and immune checkpoint blockade resistant phenotypes of human glioblastoma, that agonists of the Stimulator of Interferon Genes (STING) innate immune sensing pathway potently convert glioblastoma-infiltrating myeloid populations to proinflammatory phenotypes and mediate adaptive immunity-dependent and natural killer cell-independent curative responses. We report that STING activation induces multiple compensatory mechanisms of immune suppression, including PD-L1 upregulation across the myeloid stroma and SIRPα upregulation specifically in brain resident microglia. We found that STING activation enhances microglial phagocytic capacity, and that CD47 blockade further enhances microglial phagocytosis of glioblastoma cells. Combined STING activation and CD47 blockade further extends survival in glioblastoma murine models, and increases both antigen presenting cell presentation of tumor antigens in the brain parenchyma-draining cervical lymph nodes and cytotoxic effector cell activation in glioblastoma tumors. Together these studies support the translation of therapeutic strategies to induce both proinflammatory microenvironment conversion and initiation of antitumor adaptive immune priming in glioblastoma.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Lea, Spencer
• <p>0000-0002-6804-8567</p>

Contributors dc:contributor

• Michael Curran
• Krishna Bhat
• Joya Chandra

• Brain tumor imunology
• Immunotherapy
• Neuro-Oncology
• Innate immune sensors
• Adaptive immunity
• Neuroimmunology
• Glioblastoma

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1411

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2468