Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma
Abstract
Abstract Excessive recruitment and/or activation of regulatory T cells (Treg) into the tumour microenvironment (TME) hamper anti-cancer immunity. Targeting Tregs is therefore a promising strategy to reverse the immunosuppressive features of the TME. Here, we investigate how the development of hepatocellular carcinoma (HCC) impacts the molecular programmes of tissue-resident Tregs. Tregs residing in non-tumoral liver are metabolically inert and prone to apoptosis. Conversely, HCC-infiltrating Tregs activate the nuclear factor erythroid 2-related factor-2 (Nrf2) pathway in response to the lactate-rich TME, which couples redox homeostasis with mitochondrial function and promotes Treg metabolic activity, survival, and suppressive function. Nrf2 loss of function, through either Treg-specific Nfe2l2 ablation or systemic pharmacological inhibition, prevents intra-tumoral Treg accumulation and suppresses cancer growth. Furthermore, patients with advanced HCCs enriched in Tregs with high Nrf2 activation exhibit shorter progression-free survival following atezolizumab/bevacizumab treatment. We propose Nrf2 as a target to disrupt Treg metabolic adaptation within the TME, tipping the balance between effector and regulatory immune cells and reducing cancer progression.
Article Details
Authors (42)
E. Perpiñán
N. Sompairac
D. Marin Correa
E. Ramon-Gil
RCH Man
D. Camell-Raventos
R. Savoldelli
M. Fleming
L. Bellersheim
CX Santos
M. Elgosbi
JJ Lozano
M. Maddaloni
C. Schmidl
E. Kodela
M. Piqué-Gili
AH de Sande
R. Pinyol
S. Higginbotham
Q. Peng
E. Landman
J. Torres-Yaguana
V. Sharma
C. Zhang
A. Kurt
X. Liao
T. Dowe
M. Habarwaa
Z. Liu
Y. Zen
R. Miquel
D. Sarker
S. Kordasti
T. Tree
AM Shah
GO Fruhwirth
AT Dinkova-Kostova
EL Pearce
J. Leslie
JM Llovet
A. Sánchez-Fueyo
N. Safinia