Department of Pharmacology and Chemical Biology
Wan lab figure for JCI 2024

Investigators have identified that the anomalously high expression of CD73 in TNBC correlates with post-translational modifications (PTMs) of proteins and that the upstream protein OTUD4 is a novel target for improving the anti-cancer immune response in TNBC. Through multi-omics analyses, researchers have not only elucidated the yin-yang regulatory mechanism of CD73 in tumors—governed by the ubiquitylation by TRIM21 and the deubiquitylation by OTUD4—but also elucidate the complex biological processes that influence the entire tumor microenvironment. This research offers new insights into CD73's role in tumor immune escape and specifies how TRIM21/OTUD4 interacts with CD73 and how this interaction is modulated. Moreover, it paves new pathways for drug development targeting CD73 and its regulatory mechanisms, providing strong guidance for personalized treatment. Importantly, the Wan and colleagues developed a new type of small molecule drug, ST80, targeting the interaction between OTUD4 and CD73, demonstrating its potential to reinvigorate CD8+ T cell activity and enhance tumor sensitivity to PD-L1 treatment, suggesting that precise drug interventions can directly transform the immune characteristics of the tumor milieu. Overall, this study emphasizes the significance of a comprehensive analysis and utilization of the complexity of the tumor microenvironment for disease management. This approach could enhance the efficacy of existing immunotherapy regimens and offer new hope to patients who have developed resistance to current treatments.

The study was supported and funded by the National Institutes of Health (NIH), the National Cancer Institute (NCI), and the Emory Winship Cancer Institute Breast Cancer Research Pilot Fund.

Article Published March 5, 2024:

Wang Lab JCI figure of CD8+

"CD8+ T cells sustain antitumor response by mediating crosstalk between adenosine A2A receptor and glutathione/GPX4".

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4–dependent (GPX4-dependent) ferroptosis. Here, the Wan Lab shows the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy.

The Wan lab identifies a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Their study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.