IMMU-81. Glioblastoma and other intracranial pathologies elicit systemic sympathetic hyperactivity that limits immunotherapeutic responses

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Abstract Immunotherapies remain largely ineffective against intracranial malignancies such as glioblastoma (GBM), in part due to profound systemic and local immune dysfunction. Hallmarks of systemic immune dysfunction include bone marrow T cell sequestration, T cell dysfunction, lymphoid organ atrophy, and lymphopenia. We report that intracranial tumors, unlike their extracranial counterparts, induce chronic sympathetic hyperactivity and significantly elevate circulating catecholamine levels in both mice and human patients. In murine models, we demonstrate that intracranial tumors elicit elevated systemic catecholamine levels that result in systemic immune suppression, including impaired T cell function, lymphoid organ atrophy, bone marrow T cell sequestration, and lymphopenia. Interestingly, we also identified these phenomena amidst acute intracranial pathologies, such as stroke and traumatic brain injury. Mice harboring these intracranial pathologies also suffer immune disturbances within the thymus and bone marrow, leading to defective T- and B-cell lymphogenesis. Catecholamines act on the alpha- and beta-adrenergic receptors, which can be found on immune cells. We found that beta-agonism suppresses T cell function, while nonspecific beta-blockade with propranolol restores T cell function and favorably alters the tumor microenvironment (TME). Beta-blockade also significantly improves survival in GBM-bearing mice when combined with 4-1BB agonist and PD-1 blockade immunotherapy. Extended survival is likewise observed in retrospective analysis of nearly 9,000 GBM patients who received beta-adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received beta-blockade alongside concomitant immune checkpoint inhibition. These data suggest that sympathetic hyperactivity facilitates systemic immune dysfunction in the setting of intracranial tumors and advance a role for beta-adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment.

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