Elucidating Mechanisms of Intracranial Tumor-Driven Systemic Immunosuppression

Abstract

Intracranial tumors present unique challenges for immunotherapy. These include both local and systemic immunosuppression, the mechanistic underpinnings of which are incompletely understood. This work focuses on elucidating these mechanisms and identifying potential translational strategies to overcome these obstacles to immunotherapeutic success in intracranial malignancy. Herein, I demonstrate that intracranial tumors elicit chronic systemic sympathetic hyperactivity in the form of increased circulating catecholamine levels. I then show that this overactivation of the sympathetic nervous system (SNS) impairs T cell function throughout the body as well as at the site of the tumor. This SNS-mediated T cell dysfunction limits immunotherapeutic success. I subsequently demonstrate that treatment with -adrenergic blockade, which blocks this SNS signaling at  adrenergic receptors specifically, increases NF-B activity in immune cells, restores T cell polyfunctionality, modifies the tumor microenvironment, and licenses immune-based therapies in murine models of glioblastoma to extend survival. Extended survival is also observed in glioblastoma patients having received -adrenergic blockade, as well as in patients with melanoma and lung cancer brain metastases who received -blockade with concomitant immune checkpoint inhibition. While -blockade also impacts outcomes in the setting of extracranial disease, the benefits are especially pronounced in patients harboring intracranial disease burdens. These data suggest that sympathetic hyperactivity mediates systemic immune dysfunction in the setting of intracranial tumors and advance a role for -adrenergic blockade in licensing immunotherapeutic responses within the intracranial compartment by globally restoring T cell function throughout the body.The second aspect of my work builds on these findings to further understand mechanistic drivers of other aspects of systemic immunosuppression observed in intracranial malignancy. Along with the aforementioned T cell dysfunction, patients and mice with intracranial tumors, regardless of tumor histology, exhibit lymphopenia, lymphoid organ atrophy, and sequestration of T cells in the bone marrow. In seeking to determine the driving factors underlying these additional immune changes, I first demonstrated that non-malignant intracranial pathologies, including stroke and traumatic brain injury, also exhibit lymphopenia, lymphoid organ atrophy, and T cell bone marrow sequestration; however, these changes resolve over time in acute pathologies. Additionally, I identified defective T- and B-cell lymphogenesis as additional unifying features across intracranial pathologies, including multiple tumor types the intracranial compartment, driven by decreased cellular proliferation and increased apoptosis. In all of the models studied, intracranial pathology resulted in increased SNS and hypothalamic-pituitary-adrenal axis signaling, as measured by catecholamine and corticosterone levels. I determined that both of these signaling axes are sufficient to drive the lymphoid organ shrinkage and impaired lymphogenesis observed in these models. I found that that ⍺2 adrenergic signaling, specifically, is responsible for SNS-driven lymphoid organ atrophy and impaired lymphogensis, as opposed to T cell dysfunction, which I previously demonstrated is caused by signaling through the 2 adrenergic receptor. Lastly, I show that intracranial inflammatory signaling via IL-1 is sufficient to drive increased SNS signaling and that stimulation of the paraventricular nucleus of the hypothalamus results in lymphoid organ atrophy, implicating intracranial inflammation and hypothalamic activation as the overarching upstream drivers of this phenomenon across intracranial pathologies. In summary, my work implicates SNS hyperactivity in driving a number of immune alterations that negatively impact the anti-tumor immune response and hinder immunotherapeutic success in the setting of intracranial tumors. I show that this hyperactivity results in 1. chronic signaling through the 2 adrenergic receptor, which impairs T cell function and 2. chronic signaling through the ⍺2 adrenergic receptor, which causes lymphoid organ shrinkage and impaired lymphogenesis. SNS hyperactivation therefore represents a major obstacle that must be addressed if we are to successfully employ immunotherapy in brain tumor patients. Based on my work, combination 2 and ⍺2 adrenergic blockade represents a promising adjuvant to immunotherapy in brain tumor patients, as 2 blockade will improve the quality of the body’s T cells and ⍺2 blockade will increase the overall number of lymphoid cells in the body and maintain lymphoid organ structure and function.