GABA/Baclofen Enhances Immunotherapy of Breast Cancer by Stabilizing PD-L1

Abstract The programmed death-ligand 1 (PD-L1) on the surface of tumor cells binds to the receptor programmed cell death protein 1 (PD-1) on effector T cells, thereby inhibiting the anti-tumor immune response. Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has been approved for the treatment of human cancers with lasting clinical benefit. However, many cancer patients did not respond to anti-PD-1/PD-L1 antibody blocking therapy or drugs targeting PD-1/PD-L1. Recent studies have shown that the response to PD-1/PD-L1 blockade may be related to the PD-L1 abundance of tumor cells. Therefore, it is of crucial significance to find drugs to regulate the expression of PD-L1, which can provide new strategies to improve the response rate and efficacy of PD-1/PD-L1 blocking in cancer treatment. Here, we found that GABA and baclofen, upregulates the protein level of PD-L1 by reducing the mRNA and protein levels of STUB1 , a E3 ubiquitin ligase, thereby decreasing the interaction between STUB1 and PD-L1, and ultimately stabilizing PD-L1. Notably, GABA and baclofen did not affect cell proliferation in vitro , while in the treatment of breast cancer in mice, the therapeutic effect of baclofen combined with anti-PD-L1 antibody is significantly better than that of using anti-PD-L1 antibody alone by stimulating tumor infiltration of CD8 + T cells and antitumor immunity. Taken together, we unveiled a previously unappreciated role of GABA/baclofen in stabilizing PD-L1 and enhancing the immunotherapy of breast cancer.