# Mechanistic insights into immune suppression in brain tumors:  a role for beta-arrestin 2

> **NIH NIH F30** · DUKE UNIVERSITY · 2022 · $51,752

## Abstract

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.

## Key facts

- **NIH application ID:** 10464968
- **Project number:** 1F30CA271495-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Lucas Wachsmuth
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 1
- **Project period:** 2022-04-09 → 2025-04-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464968

## Citation

> US National Institutes of Health, RePORTER application 10464968, Mechanistic insights into immune suppression in brain tumors:  a role for beta-arrestin 2 (1F30CA271495-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10464968. Licensed CC0.

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