1055 Intracranial Tumors Elicit Systemic Sympathetic Hyperactivity That Limits Immunotherapeutic Responses

INTRODUCTION: Immunotherapies, while standard of care for certain solid tumors, suffer a relative lack of efficacy within the intracranial (IC) compartment, particularly against GBM. IC tumors present unique challenges for immunotherapy, including induction of systemic immune-dysfunction via mechanisms that are incompletely understood. METHODS: For murine studies, CT2A-gliomas, LLC-lung cancers, or B16-melanomas were implanted peripherally and intracranially. Catecholamines (epinephrine / norepinephrine) were measured in blood and spleen by ELISA, and T cell phenotypes / function assayed. For survival studies, mice were administered anti-PD-1 or propranolol alone or in combination. In patients with GBM and brain metastases, serum catecholamines were measured by ELISA. Retrospective survival studies were conducted analyzing SEER Medicare data. RESULTS: We reveal in both patients and mice that glomas, lung cancers, and melanoma harbored intracranially (but not peripherally) elicit systemic elevations in circulating catecholamines that are sufficient to drive T cell dysfunction and limit immunotherapeutic success. Conversely, treatment of IC tumor-bearing mice with nonselective b-adrenergic blockade (propranolol) increases NF-kB activity in immune cells, restores T cell polyfunctionality, and licenses immune-based therapies to extend survival. Retrospective analysis of ∼9,000 patients with GBM reveals significantly extended survival in those patients receiving b-blockers for any indication, while analysis of ∼30,000 patients with lung cancer or melanoma reveals dramatically improved survival in patients with brain metastasis who received concomitant immune checkpoint inhibition and b-blockade. CONCLUSIONS: These data suggest roles for sympathetic hyperactivity in facilitating systemic immune-dysfunction in the setting of IC tumors, specifically, and advance a role for b-blockade in licensing immunotherapeutic responses within the IC compartment.