ABSTRACT Cancers located within the brain, including both primary brain tumors and metastases, exhibit dismal prognoses and do not respond well to immunotherapy, in part due to marked systemic tumor-induced immunosuppression. Systemic immune suppression is a hallmark of IC tumors, independent of tumor type. Systemic immune deficiencies in patients and mice with IC tumors include AIDS-level lymphopenia, lymphoid organ contraction, and sequestration of T cells in the bone marrow (BM). BM T cell sequestration follows the loss of T cell sphingosine-1-phosphate receptor 1 (S1P1), a surface protein that functions as an “exit visa” mediating T cell egress from lymphoid organs. Surface levels of S1P1 can be stabilized by knocking out (KO) β-arrestin 2 (βarr2), the protein responsible for S1P1 internalization. Unexpectedly, βarr2KO mice implanted with IC tumors demonstrate an unprecedented ~50-80% long-term survival benefit in the absence of any additional intervention. Both CD4+ and CD8+ T cells are required for this enhanced survival, and T cell activating therapies further extend βarr2KO survival. These data suggest that βarr2KO mice mount an enhanced T cell anti-tumor immune response in βarr2KO mice, although the mechanism of enhanced T cell function remains unclear. For T cells to mount an effective anti-tumor immune response and clear tumors in vivo, they must activate Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). NF-κB functions as a “master regulator” of inflammation, and βarr2 is a known inhibitor of NF-κB activation. Importantly, this βarr2-NF-κB axis is regulated by the sympathetic nervous system (SNS), specifically through the beta-2 adrenergic receptor (β2AR). SNS signaling through the β2AR increases βarr2 levels and thereby prevents NF-κB activation. SNS overactivation in other IC pathologies has been linked to the same systemic immune deficits seen with IC tumors, and we have evidence of increased SNS signaling in IC tumor-bearing mice. Notably, βarr2KO tumor- bearing mice exhibit less lymphopenia and lymphoid organ contraction. Furthermore, SNS blockade abrogates BM T cell sequestration in tumor-bearing wild-type (WT) mice. Taken together, these findings suggest that 1) βarr2 plays a key role in restricting anti-tumor immune responses by inhibiting NF-κB, and 2) SNS overactivation due to IC tumors may drive increased immunosuppressive βarr2 activity. The long-term goal of this proposal is to generate mechanistic insights into tumor-driven immunosuppression that will inform therapeutic approaches to license and improve immunotherapies. The primary objectives of this proposal are to determine the impact of 1. βarr2 deficiency on anti-tumor T cell function and 2. IC tumor- driven SNS overactivation on βarr2 activity and anti-tumor immunity.