Biology subjects

Gandy, E. J.

Publications and source records attributed to Gandy, E. J..

2 recordsLinked to original sources

bioRxiv2023

Adaptive IRE1 Signaling Elicits T Cell Metabolic Remodeling and Tumor Control

The efficacy of cancer immunotherapies is limited by the metabolic instability of the tumor microenvironment (TME) that disables T cell antitumor immunity. Metabolic imbalances within the TME are sensed and responded to by stress sensors of the endoplasmic reticulum (ER) unfolded protein response (UPR). The UPR comprises three integrated signaling pathways harboring both adaptive and deleterious phases based on the extent and duration of cell stress. Here, we elucidate the differential contributions of adaptive and deleterious signaling downstream of the UPR IRE1 pathway in T cell-regulated tumor control. T cells in murine and patient cancers experience persistent ER stress, leading to hyperactive IRE1 signaling that limits tumor control. However, amplifying the adaptive arm of the IRE1 UPR serves to eliminate mitochondrial toxicity and protect T cells from chronic ER stress, yielding robust tumor engraftment and long-term tumor immunity. Our findings establish the UPRs essential protective role in antitumor immunity.

immunology↗

bioRxiv2023

Acetyl-CoA Carboxylase Obstructs CD8+ T-Cell Lipid Utilization and Energy Synthesis in the Tumor Microenvironment

The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, enforcing lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC wholly rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell memory, engendering TILs with increased survival and polyfunctionality, with the ability to control solid cancer.

immunology↗