Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.

Journal Article (Journal Article)

Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.

Full Text

Duke Authors

Cited Authors

  • Huang, D; Wang, Y; Thompson, JW; Yin, T; Alexander, PB; Qin, D; Mudgal, P; Wu, H; Liang, Y; Tan, L; Pan, C; Yuan, L; Wan, Y; Li, Q-J; Wang, X-F

Published Date

  • February 2022

Published In

Volume / Issue

  • 24 / 2

Start / End Page

  • 230 - 241

PubMed ID

  • 35145222

Pubmed Central ID

  • PMC8852304

Electronic International Standard Serial Number (EISSN)

  • 1476-4679

Digital Object Identifier (DOI)

  • 10.1038/s41556-021-00820-9

Language

  • eng

Conference Location

  • England